CD3+ T cells are important sources of both pro- and anti-inflammatory cytokines during Plasmodium falciparum malaria. We studied the frequency of interleukin-2 (IL-2), gamma interferon (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-10 expressing CD3+ cells in 10 non-immune malaria patients with uncomplicated malaria and in one patient with cerebral malaria after P. falciparum-specific and non-specific mitogenic stimulation. Analysis by fluorescence-activated cell sorting was performed after drug-induced clearance of parasites to allow previously sequestered T cells to be detected in peripheral blood. CD3+ cells of patients responded to P. falciparum infected erythrocytes with significant increases in the percentage of IL-2, IFN-gamma, and TNF-alpha, but also IL-10, positive cells. CD3+ cells from malaria-naïve donors were also responsive to specific stimulation albeit to a much lesser extent. Mitogenic stimulation of PBMC revealed no significant differences between cells of patients and controls. CD3+ cells of the patient with cerebral malaria were hyporesponsive both to the infecting parasite isolate as well as to our laboratory-adapted P. falciparum isolate, whereas two patients with uncomplicated disease were more responsive to their infecting parasites than to the laboratory-adapted isolate. The results indicate that the increased responsiveness of in vivo primed compared to malaria-naïve CD3+ cells is Plasmodium-specific and biased towards production of IFN-gamma and TNF-alpha.