We studied whether a two-dose regimen of inactivated influenza virus vaccine was more effective than a single dose in inducing protective hemagglutinationinhibition 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 μg 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 (≥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.