Human alveolar, peritoneal, and cultured macrophages were exposed in vitro to human recombinant interferon-gamma (rHuIFN-gamma) and were tested for their ability to inhibit intracellular replication of yeast-phase Histoplasma capsulatum. Exposure at various concentrations, and for different time periods, failed to activate the macrophages to inhibit multiplication of intracellular yeast. Macrophages were, however, activated by rHuIFN-gamma as shown by their ability to inhibit intracellular replication of Trypanosoma cruzi and by their enhanced production of superoxide when stimulated by phorbol myristate acetate. These data indicate that rHuIFN-gamma by itself does not activate human macrophages to inhibit intracellular proliferation of yeast-phase H. capsulatum.