We have demonstrated that monocyte-derived macrophages (M ) from HIV ϩ individuals are deficient in their capacity to phagocytose Histoplasma capsulatum (Hc) yeasts, and are more permissive for the intracellular growth of Hc. To determine whether these defects in M function were caused by HIV infection of the M and/or by pathological events associated with HIV infection, cultured normal human M were infected with the HIV-1 BaL strain. Virus production, quantified by reverse transcriptase activity and p24 antigen, was evident on day 8 after infection and peaked on day 16. On days 12, 16, and 20 after infection, HIV-1-infected M were deficient in their capacity to recognize and bind Hc yeasts compared with control M , and also were more permissive for the intracellular growth of Hc. Culture of normal M with the envelope glycoprotein gp120 inhibited phagocytosis of Hc yeasts by M in a concentration-dependent manner, but did not cause more rapid intracellular growth of Hc. Normal M cultured in the serum of HIV ϩ individuals with impaired M function subsequently were deficient in their capacity to phagocytose Hc yeasts, and were more permissive for the intracellular growth of yeasts compared with M cultured in normal serum. Conversely, culture of normal M in the serum of HIV ϩ patients with normal M function did not affect the interaction of Hc yeasts with M . Moreover, when M from HIV ϩ individuals that were initially defective in host defense against Hc were cultured in normal HIV Ϫ serum, normal M function was demonstrated. Adsorption of gp120 from the serum of two HIV ϩ patients removed the capacity of the serum to cause a M defect in phagocytosis of Hc, but had no effect on the capacity of the serum to cause accelerated intracellular growth. These data demonstrate that observed defects in M interaction with Hc yeasts may be caused by gp120 and other, as yet unknown serum component(s) probably released into serum by HIV-infected cells. (