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Roger and Mark's friend Tom Collins arrives at their building but is mugged before he can enter. Meanwhile, Roger and Mark receive a call from former friend and roommate Benjamin "Benny" Coffin III. Benny bought Mark and Roger's apartment building, as well as the lot next door. He tells them the rent is due, despite his promise to let them live there for free (Tune Up #2). Mark and Roger refuse to pay their rent (Rent).
Back at the loft, Mark tries to get Roger out of the apartment before reminding him to take his AZT (Tune Up #3). Roger attempts to write a great song to make his mark on the world before he dies of AIDS (One Song Glory).
Joanne's parents call her, wondering why she is stage managing and reminding her that she has to attend her mother's confirmation hearings (Voicemail #2). Benny arrives with an offer: if they convince Maureen to cancel her protest, he'll let them live in his new studio project, rent-free (You'll See). However, the two rebuff his offer. After Benny leaves, Angel and Collins invite Mark and Roger to attend Life Support, a local HIV support group meeting.
On their way to the show, Collins, Mark and Angel meet a peddler who gets angry with Mark for making a name for himself filming their lives but not really aiding them (On the Street). Collins talks about his dream of escaping New York and opening up a restaurant (Santa Fe). Soon after, Collins and Angel confess their love for each other (I'll Cover You). Joanne then speaks like crazy on the phone, getting everything ready for the protest (We're Okay).
Roger intercepts Mimi on her way to buy drugs, inviting her to come to the protest and dinner with them instead, to which she agrees. Meanwhile, people from the streets protest for not having a place to spend Christmas (Christmas Bells).
Maureen arrives and begins her performance: A thinly-veiled criticism of Benny through a metaphor involving a cow and a bulldog, culminating in her urging the crowd to "moo" with her (Over The Moon and Over The Moon Playoff). Benny criticizes the protest and the group's Bohemian lifestyle, declaring that Bohemia is dead. Mark and all the bohemians in the café rise up and celebrate the Bohemian lifestyle, paying tribute to everything they love, driving Mr. Grey and Benny from the café (La Vie Boheme A).
Mimi confronts Roger about ignoring her during dinner. Roger tries to explain that he has baggage, but Mimi isn't fazed. Then, as Mimi's beeper goes off (reminding her to take her AZT) she and Roger each discover that the other is HIV-positive. (I Should Tell You). Joanne returns, explaining how the evicted residents of Avenue B are rioting and "mooing" in the streets
Opening with "Seasons of Love" - a song which contemplates how to measure a year in a life - the second act takes place over the course of the year following the first act, beginning on New Years Eve.
The others finally break through the door just as Benny arrives. He says he's there to call a truce, but the group doesn't trust him. He reveals that Mimi, a former girlfriend of his, came onto him. This revelation upsets Roger and he briefly rebuffs Mimi before Angel settles everyone down. Roger and Mimi both apologize, but Mimi remains upset, and turns to the drug dealer for a fix (Happy New Year B).
Maureen and Joanne have a fight, giving each other relationship ultimatums (Take Me Or Leave Me). Maureen's flirtatious ways and Joanne's controlling behavior are too much to take, so they break up. The company sings a reprise of "Seasons of Love", as time passes and seasons change (Seasons of Love B). By spring, Roger and Mimi's relationship becomes strained. Roger keeps talking about moving out of town. Mimi comes home late again, causing Roger to believe that she is cheating on him with Benny. Roger jealously storms out, Mimi stops him and tries to tell him the truth, that she is not cheating and that she is still using drugs, but can't get the words out, and Roger leaves her (Without You). Collins continues nursing Angel who is very sick as AIDS begins to overtake him. Mark continues to receive calls from Buzzline (Voice Mail #4). Eventually, Roger and Mimi, and Joanne and Maureen, reconcile.
They then break up just as quickly. At the same time, Angel dies and Collins is heartbroken (I'll Cover You [Reprise]). Mark expresses his fear of being the only one left surviving when the rest of his friends die of AIDS (Halloween). He finally accepts the job offer from Buzzline. Roger reveals that he is leaving New York for Santa Fe, which sparks an argument about commitment between him and Mimi, and Maureen and Joanne. Collins arrives and admonishes the entire group for fighting on the day of Angel's funeral. Maureen and Joanne realize their fighting is petty, and they reconcile. Mimi tries to go to Roger, but he turns away.
Roger and Mark both have an artistic epiphany, as Roger finds his song in Mimi and Mark finds his film in Angel's memory. Roger returns to New York just in time for Christmas, and Mark quits Buzzline to work on his own film (What You Own).
Worried about their children not answering their calls, the cast's parents leave several messages on their phones (Voice Mail #5). Mimi returns about to die. She begins to fade, but not before telling Roger that she loves him (Finale A). Roger tells her to hold on as he plays her the song he wrote for her, which says that he has always loved her (Your Eyes). Mimi nearly dies: She says that she was heading into a light, but Angel told her to go back.