Alterations in macrophage oxidative burst activity following in vivo administration of recombinant murine gamma interferon (IFN-gamma), recombinant murine tumor necrosis factor alpha, and the antifungal antibiotic amphotericin B were investigated. Mice were given intraperitoneal injections of these agents alone and in combination, and the oxidative responses of their resident peritoneal macrophages to challenge with Histoplasma capsulatum or zymosan particles were measured 1 to 5 days later. Various degrees of enhanced oxidative burst activity were achieved following treatment with each agent. However, a synergistic response was observed only when mice were treated with the combination of recombinant murine IFN-gamma and amphotericin B. These results not only confirm the dual role of amphotericin as an antifungal agent and as an immunomodulator but also suggest that IFN-gamma may serve as a useful adjunct in the treatment of intracellular fungal infections.