The effect of highly active antiretroviral therapy (HAART) on T cell responses in 30 HIV-infected patients was studied. Lymphocyte proliferation in response to influenza A virus, HIV-1 p24, gp160, allogeneic leukocytes, and mitogen, as well as influenza-specific cytotoxic T lymphocyte (CTL) responses, were measured. AIDS patients had decreased T cell-proliferative responses to influenza and alloantigen compared with asymptomatic patients. Absence of positive proliferative responses of HIV-infected patients to HIV-1 antigens was not associated with increased interleukin 10 production. Correlation was observed between influenza-specific CTL response and T cell proliferation, as well as CD4+ T lymphocyte counts, indicating the importance of CD4+ helper T cells for generating antiviral CTL responses. Finally, these results show that HAART-treated asymptomatic patients, but not AIDS patients, have T cell responses comparable to those of control individuals. It remains to be determined whether immune-based therapy will contribute any additional benefit to patients who received HAART.