In BALB/c mice, liver granulomas provoked by visceral infection with intracellular Leishmania donovani are rapidly populated by influxing blood monocytes. To determine the host defense effector role of these mononuclear phagocytes, we treated three populations of infected animals with 5C6, an anti-type 3 complement receptor monoclonal antibody (MAb), which inhibits monocyte recruitment into inflamed tissues. In naive BALB/c mice, injections of 5C6 impaired the initial acquisition of antileishmanial resistance and arrested the development of mature liver granulomas. In sensitized mice with established immunity, both resistance to rechallenge and accelerated granuloma formation were similarly inhibited by MAb administration. Finally, in naive mice, 5C6 MAb also abolished the antileishmanial activity induced by treatment with the macrophage-activating lymphokine gamma interferon. Together, these results suggest a key effector role for the influxing blood monocyte in both initial and established antileishmanial defense and granuloma assembly and in the infected liver as the mononuclear phagocyte target for the antimicrobial effects of gamma interferon.