Female DBA/2 mice were found to be highly resistant to Leishmania mexicana and rarely developed lesions even when inoculated subcutaneously with high numbers (5 x 10(6] of amastigotes. Male DBA/2 mice, on the other hand, were much more susceptible to this parasite and often developed non-healing lesions even when inoculated subcutaneously with comparatively few (5 X 10(4] amastigotes. Conversely, although both male and female DBA/2 mice developed ulcerating lesions when inoculated subcutaneously with L. major amastigotes, lesions invariably healed in males but did not heal in females. Male DBA/2 mice recovered from L. major infection subsequently were found to be resistant to subcutaneous challenge with L. mexicana. Conversely female DBA/2 mice that had failed to develop lesions when infected with L. mexicana developed lesions which healed following subcutaneous challenge with L. major. Thus there is bilateral cross-immunity between L. mexicana and L. major in DBA/2 mice which overrides differences in sex-determined susceptibility to both organisms.