In experimental visceral leishmaniasis, acquired resistance is T cell-dependent, involves IFN-gamma-activated macrophages, and is expressed in the tissues by granuloma formation. Resistance also correlates with Ag-stimulated IL-2 secretion; therefore, Leishmania donovani-infected BALB/c mice were treated with anti-IL-2 mAb or rIL-2 to determine the host defense effect of IL-2. In control mice, intracellular hepatic infection peaked at 2 wk and then declined coincident with granuloma development. In contrast, liver parasite burdens in anti-IL-2-treated mice continued to increase until after 4 wk, at which time mature granuloma formation was inhibited. Treatment of mice with continuously administered IL-2 reduced liver burdens by > 50% and led to marked accumulation of granuloma mononuclear cells. The IL-2-responsive mechanism was T cell-dependent and required both L3T4+ and Lyt-2+ cells. IL-2 enhanced IFN-gamma mRNA expression in vivo and was required for IFN-gamma secretion in vitro, and anti-IFN-gamma mAb administration abolished the antimicrobial effect of exogenous IL-2. These results: 1) identify the activity of endogenous IL-2 in both antileishmanial resistance and granuloma formation; 2) demonstrate that exogenous IL-2 can enhance the granulomatous tissue reaction; and 3) indicate that IL-2 treatment stimulates intracellular antimicrobial activity largely via the induction of IFN-gamma.