Protective immunity against malaria is induced by vaccination of hosts with irradiation-attenuated sporozoites. This immunity is mediated in part by neutralizing antibodies that are directed mainly against the repeat domain of the circumsporozoite protein. Early experiments showed, however, that B-cell-depleted mice that are immunized with sporozoites can resist challenge, indicating that T-cell effector mechanisms may also have a role in protection. This idea was supported by the recent observation that protective immunity also requires T-cells expressing the CD8 antigen (CD8+ T cells) whose target is probably the developing liver-stage parasites. Moreover, an oral Salmonella vaccine that expresses the circumsporozoite protein is able to protect against murine malaria in the absence of antibodies. Here we report the identification of an epitope contained within amino acids 249-260 of the Plasmodium berghei circumsporozoite protein that is recognized by H-2Kd-restricted cytotoxic T cells. Passive transfer into mice of cytotoxic-T-cell clones that recognize this epitope conferred a high degree of protection against challenge. These results provide the first direct evidence that CD8+ T cells that are specific for a defined epitope can confer protection against a parasitic infection.