Two groups of volunteers were vaccinated by repeated exposure to the bites of Plasmodium falciparum-infected, x-irradiated mosquitoes in order to characterize the humoral and cellular immune responses of sporozoite-immunized, protected individuals. One of the two volunteers in the first immunization trial, when challenged by the bite of P. falciparum-infected mosquitoes, developed an infection only after a prolonged prepatent period. A second group of three volunteers who were exposed more frequently to larger numbers of infected mosquitoes irradiated with a lower x-ray dose was completely protected against sporozoite challenge. These individuals and the volunteer with delayed infection had high levels of antibodies to sporozoites and to the repeat region of the circumsporozoite (CS) protein. The CS-specific cellular immune responses of these volunteers were also stimulated by sporozoite immunization, as determined by proliferation of peripheral blood mononuclear cells (PBMC) and mitogen or antigen-expanded PBMC, in response to in vitro challenge with a recombinant P. falciparum CS protein. Based upon the assays used in this study, it is not possible to reach conclusions regarding specific immunologic responses and protection from sporozoite challenge.