SummaryBALB/c and BALB/c.H‐2bmice are genetically susceptible to development of persistent and severe disease following cutaneous injection of promastigotes of the protozoan parasite,Leishmania tropica major, whereas C57BL/6 are relatively resistant. Resistance in C57BL/6 can be further increased by intraperitoneal injection of living, but not killed, promastigotes prior to cutaneous challenge. Severely diseased BALB/c mice can show resistance to development of a second cutaneous lesion but apparently only in the advanced stages of systemic life‐threatening disease. A striking level of resistance to persistent disease has been demonstrated in BALB/c.H‐2bmice pre‐injected with frozen and thawedL. t. major‐infected macrophages of the continuous macrophage cell line IC‐21 (H‐2b) together withCorynebacterium parvum. No resistance is seen in recipients of eitherC. parvumor the crude antigen mixture alone. Protection is afforded by intraperitoneal andnotsubcutaneous injection of crude antigen plus adjuvant. In these vaccination studies all evidence points to the infected macrophage as the most appropriate source of ‘host‐protective’ antigens as well as being the most likely target of host‐protective immunity. Resistance is expressed in vaccinated mice as minimal signs of cutaneous disease and rapid resolution of any small lesions which do develop. Frozen and thawed promastigotes plus C. parvum will not induce resistance to persistent disease in BALB/c H‐2bmice and preincubation of promastigotes with sera from resistant vaccinated mice does not influence their capacity to cause cutaneous disease. The results provide baseline data for vaccination attempts in genetically susceptible hosts using isolatedL. t majorantigens (and, in particular, infected macrophage antigens) and highlight the utility of the intraperitoneal route of injection and the use of the therapeutic biological,C. parvum, as an adjuvant in such studies.