IL‐12 plays a key role in stimulating both innate and antigen‐specific immune responses against a number of intracellular pathogens. A neutralizing anti‐IL‐12 monoclonal antibody (mAb) was used to define and compare the role of endogenous IL‐12 in the liver and spleen of mice infected with Leishmania donovani. IL‐12 neutralization both early and late in infection caused delayed resolution of parasite load, a transient decrease in IFN‐γ, IL‐4, TNF‐α and inducible nitric oxide synthase (NOS‐2) production, and suppressed tissue granuloma formation in the liver of genetically susceptible BALB/c mice. In contrast to the liver of BALB/c mice, neutralization of IL‐12 had no effect on parasite burden in the spleen over the first 28 days of infection. However, IL‐12 appeared to be critical for the development of mechanisms which subsequently contain the growth of persistent parasites in this organ in that neutralization of IL‐12 dramatically enhanced parasite growth after day 28 of infection. Following IL‐12 neutralization, the later unchecked growth of parasites in the spleen was coincident with an extensive breakdown of the tissue microarchitecture. Immunohistochemical studies revealed that IL‐12 was largely produced by uninfected cells in L. donovani‐infected BALB/c mice. In contrast, the course of infection in the liver and spleen of genetically resistant CBA/n mice was unaffected by the administration of anti‐IL‐12 mAb. These results suggest that the liver and spleen in susceptible BALB/c mice have different temporal requirements for IL‐12 in controlling L. donovani infection, whereas IL‐12 plays little role in either organ in resistant CBA/n mice. In addition, IL‐12 appears to be involved in the generation of both Th1 and Th2 responses during L. donovani infection in BALB/c mice.