Influenza virus stimulation of leukocytes induces factors that suppress human immunodeficiency virus (HIV). The effect of influenza vaccination on influenza-induced anti-HIV activity was investigated. Influenza vaccine was administered to 25 control subjects and 20 HIV-infected patients. Antiviral activity, cytokine production, and influenza antibodies were assessed before and 2 and 6 weeks after vaccination. Immunization induced a statistically significant increase in antiviral activity in control subjects but not in HIV patients, although the number of patients who generated this activity increased. Pre- and postvaccination levels of anti-HIV activity were significantly lower in HIV patients. Vaccination of control subjects and HIV patients induced increases in production of interleukin-2 and interferon (IFN)-gamma, but not of IFN-alpha. Virus load and CD4 cell counts were not significantly altered. This study demonstrates impairment of antiviral activity in HIV patients, in addition to deficiencies in antibody responses and cytokine production. In summary, influenza vaccination can induce an increase in multiple immunologic components that remained impaired in HIV patients.