Single-dose treatment with sodium stibogluconate solution (SSG) and treatment with a nonionic surfactant vesicular formulation of sodium stibogluconate (SSG-NIV) were compared for the ability to protect BALB/c mice against infection with Leishmania donovani. Prophylactic treatment with SSG-NIV protected against infection, although its effects were time and organ dependent; protection was not obtained with SSG. Protection against reinfection with L. donovani was observed only in mice cured by treatment with SSG-NIV. However, this protective effect was probably due to the presence of residual drug rather than an immune effect, since prophylactic SSG-NIV treatment gave similar results. Transfer of enriched spleen T-cell populations from L. donovani-infected mice or from infected SSG-NIV-treated mice gave no protection against L. donovani infection in the recipients. T cells from infected mice, but not from infected SSG-NIV-treated mice, were infectious to recipients. SSG-NIV treatment was equally effective against visceral leishmaniasis in immunocompetent and SCID mice, whereas SSG treatment was less effective in the latter. The results of this study suggest that the high antileishmanial activity of SSG-NIV is due to favorable modification of SSG delivery and does not require a fully functional immune response. Cure of visceral leishmaniasis by SSG-NIV treatment in the BALB/c mouse did not protect against reinfection.