The first direct interaction between Brain and Quagmire when Brian asked Quagmire to take him and Stewie with him for his cross country tour. In the trailer, Brian and Quagmire had a nice conversation. Quagmire would eventually get himself chained to a motel bed by a crazy chick he was banging. Tired of waiting for his return, Stewie went in there and saw what was happening. Instead of saving, Stewie took the keys to the trailer and drove off with Brian, leaving Quagmire possibly for dead.
Brian sat at the bar and drank beer with Quagmire and the rest of the Beer Bar Buddies.
Brian sat at the bar and drank beer with Quagmire and the rest of the Beer Bar Buddies. Quagmire teased Brian by putting images in his head of his son, Dylan, getting hurt, causing Brian to worry and behave irrationally.
Brian was kicked out of the house and asked Quagmire if he could live with him. Quagmire accepted as long as he didn't offend the new chick he was gunna bang. However, when that chick came in, Stewie openly expressed disgust over her disfigured appearance, causing her to cry and run away. Quagmire got mad at Brian for this and snapped at him and kicked him out of the house.
Peter mentioned to Brian that Quagmire absolutely hates him, which came as a surprise to him. Peter advised Brian to stay away from Quagmire, whereas not to get into any bad blood with him. Instead of heeding Peter's warnings, Brian tried to make amends with Quagmire and get the latter to change his mind about him or at least learn why he's so hated by him. Brian would make multiple attempts to try and reach out to Quagmire, but Quagmire would just give him the cold shoulder. Many of Brian's attempts at making Quagmire like him again would only piss Quagmire off even more.
Brian would invite Quagmire out on a date and try once more to get Quagmire to like him again. Finally, Quagmire would give Brian a detailed description of why he hates him. The general gist of it was that he was egotistical, rude to his friends and family, misogynistic, opinionated, and above all things, boring. Quagmire left Brian to pay the bill as he stormed out of the restaurant, leaving his victim feeling bad about himself.
Brian was not invited to Quagmire's naval ball, unlike the rest of the Griffin family.
Upon learning that Brian had sex with his newly transitioned dad, Quagmire became instantly horrified and pissed off. He would then march on over to Brian's house, bust in, and beat the living shit out of him in a very graphic and drawn-out manner. Although Brian was initially scared of Quagmire, hoping that he wouldn't be mad at him. However, Quagmire's overall excessive and unnecessarily brutal attack on him pretty much pissed Brian off. This eventually got Brian to finally hate Quagmire in return. As Quagmire left the house, Brian made sure that even though he was beaten, bruised, and bloody, he would still get the last word. Brian said to Quagmire, "Hey, I fucked your dad." and slammed the door.
After striking out with Denise, Brian sought advice on dating women and saw that Quagmire had a dating class. Peter once again reminded Brian that Quagmire hated him and warned him not to go to the class but Brian needed the advice pretty bad, so he risked the awkward confrontation with Quagmire again. Quagmire was very cold to Brian and treated him like shit in his class by instructing him to hot on fat women and also feeding him false advice about being a dick to his date, causing her to dump him.
Brian got revenge on Quagmire by going out with his ex-girlfriend, Cheryl Tiegs and making out with her right in front of his face. Quagmire got revenge on Brian again by going out with his ex-girlfriend, Jillian Russel-Wilcox. They went on a double date which soon turned into a fight. Both of the girls broke up with their respective boyfriends and left. Both being sad about being dumped, Brian and Quagmire had a heartfelt conversation. As Quagmire got into his car, Brian asked for a ride Quagmire smiled and unlocked his car door, giving Brian the false impression that he was going to let him go for a ride, only to drive the car away before Brian could get in and then drive back to run him over.
Brian showed the courtroom the letter, addressed to him by Ida, from after she had sex with him at the Marriott. Quagmire was embarrassed and pissed when Brian showed this.
When recreating the 12 way orgy, Quagmire instructed Brian to play the role of the ugly girl at the bottom.
Peter, Brian, Quagmire, and Joe all lost their memories. Since Quagmire and Brian didn't know each other, they didn't hate each other and were just casual friends. When trying to find out who they were, Brian sniffed his own poop on Quagmire's lawn, leading him to believe that he was Quagmire's dog and so he went to live with him. Quagmire was okay with Brian being his pet at first but Brian turned out to be really annoying, getting Quagmire to hate him again.
Quagmire attended Brian's funeral and was on his phone the whole time, completely uninterested. Quagmire interrupted Peter's eulogy, by commenting on how David Ortiz kept swinging at curveballs.
Quagmire became good friends with Vinny, saying that he was much better of a dog than Brian.
Stewie assumed that Quagmire was the Car Driver that killed Brian and did an investigation on him. Quagmire said that as much as he wished he could have been the one who killed Brian, he was having sex with a lady at that time, which cleared his name of the murder. A flashback showed Quagmire having sex with a girl on his couch and seeing the road out the window, while he was doing her. He witnessed the car strike and kill Brian and he cheered with glee, upon witnessing it. Quagmire jokingly quoted "And I thought I was good at smashing bitches." to which the girl he was having sex with replied with "That doesn't work because he's a male dog." Quagmire looked down at her and said "Hey! Are you talking or sucking?"
Brian hit a fire hydrant and later, rock bottom when his face became mutilated. Brian was crying his eyes out at the bar and Quagmire spotted him. Although Quagmire hated Brian's guts, he couldn't bring himself to leave him there and gave him a ticket to a plastic surgeon to help him. Brian was grateful to Quagmire for his kind gesture but Quagmire wanted him to keep it a secret, not wanting people to know that he did something nice for him.
Brian got himself the surgery he needed to get a giant smile and then later became a realtor, being able to manipulate people into buying homes with his "realtor smile". Wanting to make a few more quick bucks, Brian tricked Quagmire into buying a highly expensive and really crappy hotel. Quagmire was disappointed with the quality of his hotel and wanted to find Brian to get a refund. He wasn't mad at him as he trusted he didn't screw him over on purpose. However, Quagmire spent all of the next 48 hours looking for Brian, while Brian hid from him to avoid making the return.
On the final hour, Quagmire finally found Brian and asked for a refund. Brian made a cheesy speech about how he was sorry he sold him a crappy hotel but he only did it because he wanted to do something nice for a friend even if that nice thing was kind of "empty". Quagmire bought this apology and forgave Brian, saying that he now sees the humanity in him. Just then, Brian's watch went off and Brian smugly said to him with a dochey attitude that he just passed the point of no return and now he's stuck with the crappy hotel forever, proving that he was just being a dick the entire time. Quagmire got so furious at Brian, that he picked up a metal chair and slammed Brian in the face, knocking all of his fancy new teeth out and reverting his face back to it's previous, mutilated state only this time, it was even uglier.
When Quagmire heard about Bonnie having an affair with Brian, he said that Brian was an absolute dick for stealing Joe's wife. He was also present at the intervention, where everybody chastised the two for being together. Quagmire didn't hold Bonnie even slightly accountable for cheating on Joe. Many could argue that if he did, it would be hypocritical, as he's had sex with Bonnie before, but it was probably mostly because he hated Brian and just wanted to seize the opportunity to guilt-trip him as much as possible.
Brian spied on the apartment across the street from his own and saw Quagmire having sex with a married woman and then escaping when her husband came home. As Quagmire escaped through the balcony fire exit, he managed to see Brian in his hotel and flipped him off.
Quagmire was brought to tears, when Brian married Jess to make her last days on earth as happy as possible. Quagmire said that he couldn't bring himself to dislike Brian anymore, knowing what a good guy he was and as a token of his appreciation, threw him the biggest bachelor party ever.
Quagmire and Brian both try to get the rich old millionaire, Pip's inheritance and compete for the money. In the end, Pip dies from a heart attack, while skydiving and the money goes to Brian. Quagmire, thinking Brian killed her (which he didn't) goes to Brian to say that he's very afraid of him and Brian, now having confidence, tells Quagmire to watch his step around him.
Brian and Quagmire run against each other for the mayor of Quahog and they both mud fling at each other to make the other candidate look stupid. Brian ends up looking like the bigger ass, while Quagmire kills it in the polls. Quagmire takes Brian for a ride in his mayoral bus and he insults him, comparing him to Ubu from the commercials. Brian gets into a fist fight with him, causing the bus to swerve off a cliff and for them both to crash. While they both await death, they have a nice conversation and actually start acting a little nice to each other.
Quagmire gets mad at Brian for dating his dad again but Ida forced them to make up and become friends. They go to a museum together and do not get along. In the end, Ida breaks up with Brian.
Brian tries to get Courtney's number but Courtney says that she's not allowed to accept the numbers of anyone unless her dad approves. Quagmire tells Brian that he's been denied and calls him an "ass".
When Brian discovered Quagmire opening a cat cafe in Quahog, it enraged Brian Griffin put his foot down and protested to be shut down. After while when it shut down and Quagmire burn dead cats in a pile he took his anger and frustration out on a grumpy Brian Griffin for for being banned as a dog in any area of Quahog. When they were fighting Brian took a big bite on Quagmire's arm to escape and got hit by a bus but shocked by Quagmire to help him in his Aid they both apologized dog walked into the night, does ending their rivalry for good.