The circumsporozoite (CS) protein is a candidate vaccine antigen for the sporozoite stage in the life cycle of the malaria parasite. Using CS protein purified from recombinant baculovirus-infected cells and a panel of H-2 congenic mice, we are able to demonstrate that this protein is poorly immunogenic in terms of antibody production as a result of Ir gene control. The immune response to the protein is also restricted following immunization with a CS-recombinant vaccinia virus or with sporozoites. Using a panel of overlapping peptides spanning the entire protein, we are able to show that the high responder mice recognize helper T cell epitopes from the same region of the protein as do humans. This region, however, is the polymorphic segment of the protein, which has implications for vaccine development. However, the close overlap of human and murine T cell epitopes demonstrates that murine models may be very useful in epitope mapping and vaccine development for human pathogens. The T cell antigenic regions of this protein fulfil the predictive requirements for the amphipathic helicity algorithm.