It is well established that a fully competent immune response is required for the successful drug treatment of visceral leishmaniasis. However, recent studies have cast some doubt as to which elements of the immune response synergize with chemotherapeutic treatment. The role of the Th2 response and IL-4 in particular during visceral leishmaniasis awaits clarification. We, therefore, examined the effectiveness of sodium stibogluconate treatment on Leishmania donovani infection in BALB/c wild-type and IL-4-/- mice. Parasite burdens in L. donovani-infected IL-4+/- and IL-4-/-, as we have previously shown for B6/129 mice, were similar, despite an apparent type 1 antibody response in infected IL-4-/- mice, demonstrated by increased levels of parasite-specific IgG2a and decreased IgG1. Unexpectedly IL-4-/- mice responded poorly to sodium stibogluconate treatment with increased parasite burdens in all tissues examined. Furthermore, drug therapy of IL-4-/- but not IL-4+/+ mice resulted in significant reductions in splenocyte IFN-gamma mRNA transcripts and in serum IFN-gamma levels. These results demonstrate that IL-4 has an important role in effective anti-leishmanial chemotherapy which seems to be related to modulation of IFN-gamma production.