TNF-alpha has been implicated in cytokine-induced macrophage activation and tissue granuloma formation, two activities linked to control of intracellular visceral infection caused by Leishmania donovani. To determine the role of TNF-alpha in L. donovani-infected BALB/c mice, we measured TNF-alpha levels and treated mice with either anti-TNF-alpha antiserum or TNF-alpha. TNF-alpha activity in infected livers was increased by 2.7-fold 2 wk after challenge and by 5.5-fold at wk 8. In parallel, although control mice acquired resistance by wk 4 and resolved infection by wk 8, liver parasite burdens steadily increased in anti-TNF-alpha-treated animals. Hepatic granuloma formation, however, was not impaired by anti-TNF-alpha. Endogenous TNF-alpha levels provoked by L. donovani appeared sufficient and optimal because exogenous TNF-alpha administration had no beneficial effect on established infection and continuous high-dose treatment impaired antileishmanial activity. Thus, although not required for granuloma formation, endogenous TNF-alpha appears to be critical to both initial acquisition of resistance to L. donovani and resolution of experimental visceral infection.