The outcome of experimental Leishmania major infection in mice is closely correlated with the type of CD4+ helper T cell (Th) response. Whereas a Th1 response is host protective, a Th2 response leads to a disseminated, fatal course of disease. Previous studies in this murine model have shown, that the two prominent Th1 and Th2 cytokines, interferon (IFN)-gamma and interleukin (IL)-4, themselves play a major role in the determination of the resulting Th response. Treatment of susceptible mouse strains (BALB/c) with anti-IL-4 induces a Th1 response, allowing the animals to cure the infection. Treatment of resistant strains (e.g. C3H/HeN) with anti-IFN-gamma induces a Th2 response with dissemination of the disease. In this report, we investigated the course of infection and Th response in susceptible and resistant mice treated with anti-IL-4 and anti-IFN-gamma simultaneously. Both mouse strains showed an initial exacerbation of the disease and an overall reduced cytokine response early after infection. Later during infection both strains had a strong Th1 response that was resulting in cure of disease in C3H/HeN mice. BALB/c mice however, could not control the spread of infection despite the strong Th1 response.