Peripheral blood lymphocytes from donors previously unexposed to malaria parasites proliferate in vitro when stimulated with whole parasitized red blood cells of several different strains of Plasmodium falciparum. Here we show that both cells enriched for both memory (CD45R0+) and naïve (CD45R0-) phenotype can respond. Cells involved in these responses occur at frequencies similar to those observed for recall antigens such as tetanus toxoid but at lower frequencies than observed for the superantigens staphylococcal enterotoxin B or the mitogenic lectin phytohemagglutinin (PHA). Proliferation is inhibited by antibodies to class II MHC and to CD3 molecules. Stimulation of purified CD45R0- T cells by whole parasitized red blood cells for 6 days results in the generation of a large proportion of gamma delta T cell blasts of V gamma 9V delta 2 TCR phenotype and in the acquisition of the CD45R0 molecule within the blast cell population. The rapid generation of a vigorous primary in vitro gamma delta T cell response by malarial parasites may reflect the situation during primary malarial infection.