Since high-dose corticosteroid therapy appears to impair cellular defense mechanisms, this study examined its effect on human monocyte function. Fifteen normal volunteers were studied before and after a three-day course of prednisone therapy (50 mg every 12 hours for six doses). A transient period of monocytopenia occurred during the first few hours of therapy. Monocyte killing of Staphylococcus aureus was reduced in nine subjects from 5.6 plus or minus 0.2 (plus or minus S.E.) X 10-6 organisms before to 1.3 plus or minus 0.4 x 10-6 organisms at completion of therapy (p less than 0.01). Similary, killing of Candida tropicalis four subjects fell from 9.3 plus or minus 0.6 to 0.6 plus or minus 0.3 x 10-6 organisma (p less than 0.01). Bactericidal activity returned to normal levels 48 hours after the last dose of prednisone. These same monocyte preparations had normal or increased chemotactic response, phagocytic rate of cryptococci, hexosemonophosphate-shunt response to phagocytosis and ultrastructural characteristics. This impairment of bactericidal and fungicidal activity during prednisone therapy may contribute to the infectious complications seen in patients receiving comparable doses of corticosteroids.