Studies with Leishmania donovani in the mouse have demonstrated that an intact T cell compartment is required for effective anti-leishmanial therapy using pentavalent antimony compounds such as Pentostam (sodium stibogluconate), suggesting that the in vivo efficacy of drug treatment is at least partially immune-based. Similarly, Leishmania-infected, immunodeficient human patients including those with acquired immunodeficiency syndrome (AIDS) generally relapse following therapy with antimonials. However, sodium stibogluconate is directly parasiticidal in vitro, in the absence of T cells or T cell products. Using a model of a cutaneous form of leishmaniasis, in which susceptible BALB/c mice were infected with Leishmania major, we investigated whether the antileishmanial activity of the drug demonstrated a requirement for interferon-γ (IFN-γ), a cytokine produced during a T helper cell type 1 (Th1) immune response and known to contribute to resistance to infection, and whether drug therapy affected the nature of the antileishmanial response. Lesion development was suppressed in mice treated from the onset of infection with sodium stibogluconate alone, and in animals treated with sodium stibogluconate plus a neutralizing anti-IFN-γ antibody, and tissue parasite burdens were approximately 10,000-fold less at the end of therapy in both groups compared with controls. Lesion development was similarly suppressed in mice with established lesions treated with either sodium stibogluconate alone, or sodium stibogluconate plus anti-IFN-γ antibody. The production of IFN-γ by cells from infected animals was somewhat increased immediately following therapy with sodium stibogluconate, an effect that was not long-lasting, while interleukin-4 (IL-4) production was not affected by treatment. Treatment with anti-IFN-γ antibody alone significantly suppressed IFN-γ production, and led to very high levels of serum IgE, demonstrating that the antibody was effective in vivo. We conclude that sodium stibogluconate activity can be readily demonstrated in IFN-γ-depleted mice infected with L. major, and that a short course of sodium stibogluconate treatment does not markedly affect IFN-γ or IL-4 production.