Natural immunity may be involved in controlling viral spread in hosts infected with HIV. A panel of gamma delta T cell receptor-positive lymphocyte clones was isolated from the peripheral blood of healthy HIV- donors and tested for anti-HIV cytotoxic responses. Twelve of 30 (40%) V gamma 9+/V delta 2+ T cell clones, but none of seven V delta 1+ T cell clones, displayed lytic activity against HIV-infected cells. The V gamma 9+/V delta 2+ clones cytotoxic for HIV-infected cells also lysed Daudi cells. However, not all V gamma 9+/V delta 2+ clones which lysed Daudi targets had the capacity to lyse HIV-infected cells. Some of the gamma delta T cell clones were also investigated for potential proliferative responses to HIV-infected cells. One V gamma 9+/V delta 2+ T cell clone (ME8-7) and one V delta 1+ T cell clone (ME18-2) demonstrated proliferative responses towards HIV-infected cells. Another V gamma 9+/V delta 2+ clone (VM39) proliferated in response to cell-free HIV. Taken together, these results provide direct evidence of anti-HIV gamma delta T cell responses in healthy, HIV- persons.