In the 1980s, substantive experimental data and emerging clinical results suggested that interferon-gamma (IFN-gamma), a T-cell-derived lymphokine with broad macrophage-activating effects, had considerable potential in the treatment of nonviral infections as a host defense-enhancing antimicrobial agent. During the past 6 years, the breadth of the experimental activity with IFN-gamma against nonviral pathogens has been expanded still further, and pilot studies and formal clinical trials using IFN-gamma have been undertaken in the treatment of patients both at risk for and with active infections. Thus far, IFN-gamma has been approved for use as prophylaxis in patients with chronic granulomatous disease. However, IFN-gamma also appears effective as adjunctive therapy for at least one disseminated intracellular infection (visceral leishmaniasis), and in conjunction with conventional therapy, may benefit patients with certain forms of cutaneous leishmaniasis, disseminated Mycobacterium avium complex infection, and lepromatous leprosy. Despite a rationale for its use, IFN-gamma has not yet been tested in tuberculosis or fungal or common bacterial infections nor sufficiently examined in the prevention and/or treatment of the opportunistic infections related to acquired immunodeficiency syndrome. IFN-gamma remains a promising host defense-enhancing cytokine with still unexplored clinical potential.