The major surface glycoprotein (gp63) of Leishmania major incorporated into the immunostimulating complexes (ISCOMs) was used to protect Balb/c mice against experimental infection. Two intraperitoneal vaccinations with low doses of gp63 into ISCOMs (gp63-ISCOMs) induced protective immunity in vaccinated mice as indicated by reduced inflammation and suppressed lesions after experimental challenge. An augmented IgG-specific secretion and a specific switching towards the IgG2a isotype was observed in the serum of vaccinated mice. Gp63-ISCOMs primed spleen cells restimulated in vitro with soluble Leishmania antigen (SLA) or live parasites displayed strong gp63-specific proliferative responses and secreted high levels of interleukin-2, interferon gamma and interleukin-10 but not interleukin-4. No delayed type hypersensitivity response to either SLA or LV39 was detected. These data indicate that gp63-ISCOMs induced a protective immunity in the susceptible Balb/c mice against Leishmania challenge, modulating the immune response towards a Th1 rather than Th2 type.