Depression and alcohol abuse have been associated with alterations in cell-mediated immune function. This study directly compared the effects of depression, alcoholism, and their joint contribution to reduce natural killer cell cytotoxicity. Natural killer cell activity was significantly lower in both depressed (n = 18) and alcoholic (n = 19) patients compared with control subjects (n = 50). In addition, patients with a dual diagnosis of either alcohol abuse and secondary depression (n = 9) or depression with a history of alcohol abuse (n = 26) demonstrated a further decrease in natural killer cell activity compared with that found in patients with either depression or alcoholism alone. While both depression and alcoholism are separately associated with a reduction of natural killer cell activity, subgroups of patients in whom the diagnoses of alcoholism and depression coexist show a further decrement in natural killer cell function.