The phagocytic and fungistatic activity of monocyte-derived macrophages from human immunodeficiency virus (HIV)-positive persons against Histoplasma capsulatum yeasts was determined. Macrophages from HIV-positive patients were profoundly deficient in their capacity to recognize and bind H. capsulatum, but ingestion of bound yeasts was normal. The binding of H. capsulatum by patient macrophages tended to decrease with a decrease in CD4+ T lymphocyte counts. Another major defect was that patient macrophages were more permissive for the intracellular growth of H. capsulatum. Macrophages from 22 of 58 patients showed a > or = 2-fold increase in intracellular growth compared with control macrophages. Thus, in addition to defects in cell-mediated immunity caused by a loss of CD4+ T cells, macrophages from HIV-positive patients exhibit intrinsic defects in macrophage function against H. capsulatum that may contribute to the increased susceptibility of HIV-positive patients to disseminated histoplasmosis.