To explore the role of antibody-dependent cellular cytotoxicity (ADCC) in controlling HIV-1 infection, ADCC was compared with plasma RNA and CD4⁺ cell count in 40 patients not receiving antiretroviral therapy and in seven patients after the initiation of treatment. Among untreated patients, ADCC effector cell function of peripheral blood mononuclear cells, measured by ⁵¹Cr release assay, correlated inversely with viral load (R = -0.42, p = 0.007) and directly with CD4⁺ cell count (R = 0.52, p = 0.001). On the other hand, HIV-1-specific ADCC antibody level correlated directly with viral load, but only among patients with high CD4⁺ cell counts. Therapy-induced changes in ADCC effector cell function correlated strongly with changes in CD4⁺ cell count (R = 0.86, p = 0.014), whereas there was no consistent pattern of change in ADCC antibody with therapy. In a novel assay, ADCC reduced virus yield from CD4⁺ lymphocytes infected with a primary HIV isolate. ADCC may contribute to control of viremia, and CD4⁺ lymphocytes likely play a role in ADCC effector and antibody functions.