The effect of forskolin, a unique adenylate cyclase activator, on antibody-dependent cell-mediated cytotoxicity (ADCC) was examined. ADCC was assayed using Chang liver cells as the target cells, immuned rabbit serum as the antibody and healthy human peripheral blood mononuclear cells (PBMNC) as the effector cells. Forskolin at concentrations ranging from 1 to 20 microM significantly inhibited ADCC in a dose-dependent manner. By the addition of forskolin, cyclic AMP levels did not change in Chang liver cells but increased in PBMNC. Therefore, it appears that forskolin exerted an inhibitory effect on ADCC by increasing the intracellular cyclic AMP levels in PBMNC, the effector cells.