We studied whether a two-dose regimen of inactivated influenza virus vaccine was more effective than a single dose in inducing protective hemagglutination-inhibition antibody responses in patients infected with human immunodeficiency virus (HIV). Participants included subjects with acquired immunodeficiency syndrome, subjects with acquired immunodeficiency syndrome-related complex, and HIV-seropositive individuals with either lymphadenopathy only or no symptoms. Control subjects were HIV-seronegative heterosexuals and HIV-seronegative homosexuals. Two doses of inactivated influenza vaccine containing 15 micrograms of the hemagglutinin of influenza A/Taiwan/1/86(H1N1), A/Leningrad/360/86(H3N2), and B/Ann Arbor/1/86 were administered intramuscularly in the deltoid region 1 month apart. The second dose of vaccine did not significantly increase the frequency or magnitude of antibody responses of either HIV-seropositive or HIV-seronegative subjects over that achieved by a single dose. The two-dose regimen induced a protective level (greater than or equal to 1:64) of hemagglutination-inhibition antibody to influenza A(H1N1) or (H3N2) virus less often in subjects with symptomatic HIV infection than in uninfected control subjects (39% vs 87% or 46% vs 97%, respectively). Our results suggest that a substantial proportion of individuals with symptomatic HIV infection might remain unprotected from influenza, even after immunization with a two-dose regimen.