We have investigated the phenotype of human lymphocytes responding to a defined Plasmodium falciparum malaria antigen in vitro. Cells were obtained from the peripheral blood of malaria-immune donors from an endemic area of West Africa and were tested for proliferation in response to cloned fragments of a merozoite surface protein (PfMSP1). Depletion and inhibition studies indicated that the majority of proliferating cells were CD4+ and restricted by HLA-DR or -DQ. A proportion of responding cells appeared to be CD8+, but their response was dependent on help from CD4+ cells. In two donors there was evidence that low responses could be enhanced by removal of CD8+ cells and/or blocking of antigen presentation by anti-HLA-DQ antibodies. This phenomenon was observed in cells collected during the wet (malaria transmission) season but not in cells collected from the same individual during the dry season.