The beta-adrenergic receptors were studied in vitro in lymphocytes obtained from patients with major affective disorders and controls. Specific L-[3H]-dihydroalprenolol binding was decreased in both depressed and manic patients compared to controls and euthymic patients. Isoproterenol-stimulated, but not prostaglandin El-stimulated, cyclic adenosine-3',5'-monophosphate production was decreased in manic and depressed patients. These results suggest decreased lymphocyte beta-receptor functioning in depression and mania. This decrease may be an index of changes in brain beta-receptors in mania and depression, or may simply reflect homeostatic regulation of peripheral beta-receptors in response to stress-induced increases in circulating catecholamines.