Human peripheral blood T-cells mount vigorous proliferative responses to asexual stage parasites of P. falciparum regardless of whether the donor has been exposed to the parasite. Here using highly purified P. falciparum gametocytes lye show that the same is also true for this stage of the parasite. Gametocytes, like immature trophozoites, preferentially activate CD4(+) T cells. gamma delta T-cell activation, commonly observed in response to mature schizonts or supernatants from asexual-stage cultures, does not occur. Furthermore, the CD4(+) T-cell blasts stimulated by gametocytes show a similar pattern of T-cell receptor variable region (TCRV beta) usage to those stimulated by asexual parasites and there is no preferential usage of TCRV beta elements. The CD4(+) T-cell precursor frequencies for game tocyte and asexual trophozoite responses are remarkably similar. 'Cross-reactivity' of gametocyte and asexual stage responses was confirmed by selective depletion of cells responding to particular stages of the parasite using the cytostatic drug cytosine arabinoside (Ara-C). These results suggest that the CD4(+) T-cell responses from malaria nonexposed donors are common to gametocytes and asexual trophozoites.