We have characterized the immune response of mice to multiple Ag peptide systems (MAP) containing the immunodominant B cell epitope (NANP)3 and one of three distinct Th epitopes, Th2R, Th3R, and CS.T3, of the C terminal region of the circumsporozoite protein of Plasmodium falciparum, a human malaria parasite. Mice of three different MHC haplotypes (H-2k, H-2d, and H-2a) were immunized with the various MAP constructs. Mice of all three strains produced antibodies, but their anti-sporozoite titers were considerably lower than their anti-peptide titers as detected by ELISA. These antibodies reacted at high titers not only with the repeat polymer (NANP)50, but also with MAP that contained only the respective Th sequence. The antibody binding site within each of the Th sequences was mapped, using truncated peptides, in an inhibition assay. A primary antibody response, induced by a single i.v. inoculation of sporozoites, was greatly enhanced by the injection of MAP.