Proliferative responses of peripheral blood lymphocytes to synthetic peptides representing major epitopes of two malaria antigens (the merozoite ring-infected erythrocyte surface antigen and the sporozoite circumsporozoite protein) were investigated in Madagascar during a clinical Plasmodium falciparum episode. Thirty-seven patients greater than 10 years of age were enrolled at the beginning of the malaria transmission season and followed for four weeks. At enrollment, when the subjects presented with an acute infection, lymphocytes recovered from approximately 30% of them proliferated after peptide stimulation. These proliferative responses decreased sharply one and two weeks after treatment, with less than 10% responding to each peptide. Four weeks after treatment, the responses were only partially restored. The amplitude of these variations was not related to the initial parasitemia. At the individual level, proliferative response to each peptide varied greatly during the followup period, and this variation was unrelated to the presence of parasites in the blood.