Cell-mediated immunity is affected early in human immunodeficiency virus type 1 (HIV-1) infection. HIV-1—specific CD4⁺ T cell proliferative responses are not measurable in most patients but have been reported in long-term nonprogressors and in patients treated with highly active antiretroviral therapy (HAART) during primary infection. However, treatment with HAART generally does not restore HIV-1—specific CD4⁺ T cell responses in chronically infected patients. In this study, HIV-1—specific CD4⁺ T cell responses in 10 HIV-1—infected patients who began HAART with low CD4 cell count nadirs and experienced significant immune reconstitution were studied. Surprisingly, 5 of these patients had proliferative responses to ⩾1 HIV-1 gene product, compared with 0 of 8 chronically infected patients who started HAART when their CD4 cell counts were still relatively high. These results suggest that, in some patients with advanced HIV-1 infection, treatment with HAART can lead not only to significant increases in CD4 cell counts but also to the restoration of HIV-1—specific responses.