Season 2 begins with Masters dealing with the ramifications of his disastrous presentation and being fired from the hospital. Meanwhile, Libby urges Masters to get another job; and Virginia fights off advances and innuendos stemming from the belief that she was the woman in Master's explicit film.
Masters begins a new job at Memorial Hospital under Betty's extortion terms only to discover that his boss insists he leave Virginia behind in favor of a handpicked secretary. Meanwhile, Johnson is torn between pressing Masters to rehire her and staying by DePaul's side as her condition worsens.
Johnson tries to cover when she and Masters are seen by Langham leaving a hotel together after an evening tryst. Later, Masters attempts to bring Johnson aboard as his assistant at his new post; and Betty tries to conceal her infertility from Gene, over Masters' objections.
Masters breaks new ground by continuing his study as the only white physician in a black hospital but at the cost of his gynecology practice. Meanwhile, Libby is confronted by Robert over her poor treatment of his sister Coral; Betty reunites with her former lover; and Johnson struggles to right her relationship with DePaul, who is now aware of her ongoing affair with Masters.
Hendricks bans Masters from using black participants in his study, but Masters contacts a journalist to aid his efforts. Meanwhile, Johnson is forced to accept DePaul's choice to end her chemotherapy treatments; Gene learns the truth about Betty and Helen's relationship; and Libby fires Coral after discovering she lied about Robert being her lover.
Masters becomes impotent without Johnson's knowledge, after learning that she is continuing to have romantic relationships with other men, so he cuts off their sexual work together. Meanwhile, Masters tries to keep his new clinic solvent by borrowing against his house and offering medical services to the hotel.
Masters bristles at Frank's insinuations about his and Estabrooks' demons; Virginia uses a patient's case history to gain advice from a psychiatrist; Betty and Masters try to remedy Lester's impotence by hiring a prostitute; Barbara gets an unsettling diagnosis that threatens to expose a chain of secrets.
Johnson tries to find a cure for Masters' sexual difficulties; Masters learns of a rival study and tries to brand his work; Flo informs Langham that he must have sex with her in order to keep his job; Barbara and Lester connect over their shared sexual dysfunctions; Libby asks Johnson to give her an alibi while she canvases a tenement for a rent strike with CORE.