The lack of a simple, rapid, and quantitative test of the functional activity of the monocyte has hampered studies of the contribution of this cell type to host defense and human disease. This report describes an assay of antibody-dependent cellular cytotoxicity, which depends exclusively upon the monocyte as the effector cell and therefore provides a convenient test of monocyte function. In this system, mononuclear leukocytes (MNL) obtained by Ficoll-Hypaque separation of whole blood are cytotoxic for 51Cr-labeled human erythrocyte targets coated with anti-blood group antibody. Removal of phagocytic monocytes from the MNL by iron ingestion, followed by exposure to a magnetic field, completely abolishes all cytotoxic activity from the remaining MNL population. Similarly, in severely mono-cytopenic patients with aplastic anemia, cytotoxic effector activity is absent. In normals and less severely monocytopenic aplastic anemia patients, cytotoxicity correlates significantly (p less than 0.001) with monocyte number. Application of this monocyte-mediated antibody-dependent cellular cytotoxicity assay to the study of patients with the Wiskott-Aldrich syndrome has revealed defective monocyte cytotoxic activity in spite of normal monocyte numbers, suggesting that this test may be useful for the assessment of monocyte function in a variety of clinical situations.