SummaryImmunity to Leishmania donovani is associated with an interleukin (IL)‐12 driven T helper 1 (Th1) response. In addition, the ability to respond to chemotherapy with sodium stibogluconate (SSG) requires a fully competent immune response and both Th1 and Th2 responses have been shown to positively influence the outcome of drug treatment. In the present study, the influence of IL‐18, which can modulate both interferon (IFN)‐γ and IL‐4 production, on the outcome of primary L. donovani infection and SSG therapy following infection was assessed using BALB/c IL‐18‐deficient and wild type mice. IL‐18 deficiency was associated with an increased susceptibility to L. donovani infection, evident by day 40 post infection, resulting in higher parasite burdens in the spleen, liver, and bone marrow compared with wild type control animals. Infected IL‐18‐deficient mice had significantly lower splenocyte concanavalin A (ConA) induced IFN‐γ production as well as lower serum IL‐12 and IFN‐γ levels, indicating a reduced Th1 response. However, drug treatment was equally effective in both mouse strains and restored serum IL‐12 and IFN‐γ levels, and IFN‐γ production by ConA stimulated splenocytes of IL‐18‐deficient mice, to levels equivalent to similarly treated wild type mice.