Plasmodium falciparum stimulates peripheral blood gamma delta + T cells from unexposed donors. The responding cells bear V gamma 9+ chains of the T cell receptor, the majority of which, but not all, are associated with V delta 2 chains. We have analyzed whether the precursor frequency of these V gamma 9+ cells approaches that expected of superantigens or mitogens and whether, like a superantigen, the response is major histocompatibility complex (MHC) unrestricted. Limiting dilution analyses of the response of enriched gamma delta + T cells to P.falciparum using autologous and heterologous antigen-presenting cells suggest that the response is more characteristic of an antigen-specific MHC-restricted response. The frequencies are lower than would be expected if all V gamma 9+ cells respond, and there is a dramatically reduced response when allogeneic antigen-presenting cells are used.