BALB/c mice are susceptible to cutaneous leishmaniasis upon infection with Leishmania major while C57BL/6 are not. There is a major promastigote surface protease (PSP or gp63) which is available in both native and recombinant forms, and for which the primary amino acid sequence is known. Immunization with PSP has been shown to offer some protection against challenge with the live organism. Therefore, we attempted to develop a peptide vaccine with PSP peptides. In the first experiments, recall proliferative responses to PSP were measured using a set of 15mer peptides spanning the entire PSP molecule which allowed designation of major determinant regions in BALB/c, C57BL/6, and CBA mice. Several of these determinants were promiscuous and shared almost the identical core amino acid residues in the different strains. Immunization with major determinant peptides was recalled vigorously with L. major soluble antigen as well as with PSP. The response to peptide was almost entirely Th1 as measured by a localized ELISA assay for single-cell production of IFN-gamma. A similar assay for IL-5, which overcomes problems of sensitivity and inhibition by lymphokines produced by Th1 cells, indicates very little production of Th2 cells even by BALB/c. It was found that if a major responsive peak was examined by recall with overlapping peptides, the highest, central peptide gave a mainly Th1 response while the boundary, less efficient peptides gave more of a Th2 response. Possible reasons for this were discussed. These results point to the importance of selecting the exactly appropriate peptide in considering a vaccinogen that might protect susceptible individuals. Even the choice of a somewhat immunogenic peptide within the determinant envelope might actually exacerbate infection by steering the response in a Th2 direction.