Studies in mice have shown that cytotoxic T lymphocytes (CTL) specific for epitopes within the circumsporozoite (CS) protein of malaria sporozoites can prevent malaria probably by destroying infected hepatocytes. This has provided a model for the development of a sporozoite vaccine. It has not been shown whether humans can mount a CTL response to this protein nor what determinants on the protein could be considered as target epitopes for such cells and thus merit inclusion in a sporozoite vaccine. We have used a novel technique to study a caucasian population which would benefit from a sporozoite vaccine and have been able to demonstrate that some individuals with a history of sporozoite exposure do contain peripheral blood CTL specific for the Plasmodium falciparum CS protein. The prevalence of CTL among different individuals is low and there is evidence that recent malaria exposure may be a prerequisite for finding such CTL. In three individuals, CTL could be repeatedly found and in all cases the epitopes mapped to one of the two polymorphic C-terminal domains. Using a CTL line, we mapped a recognition site to residues 351-395 of the CS protein, overlapping the region of the protein recognized by murine CTL.