The effect of tumor necrosis factor alpha (TNF alpha) on lymphocyte beta 2-adrenergic receptor response is reported. Isoproterenol-mediated cyclic-3,5-adenosine monophosphate (cAMP) production by intact lymphocytes preincubated with isotonic buffer or TNF alpha was studied. TNF alpha at 1 ng/ml and 100 ng/ml reduced isoproterenol-stimulated cAMP generation by 15% and 27% over the respective basal values. Stimulation of lymphocytes with forskolin or prostaglandin E1 was minimally affected, indicating that the effect of TNF alpha was due neither to nonspecific toxicity nor to its influence on the nucleotide regulatory protein complex or the catalytic adenylate cyclase component of the beta 2-adrenergic receptor complex system. Rather, TNF alpha appeared to affect the receptor recognition unit specifically. TNF alpha causes homologous desensitization of lymphocyte beta 2-adrenergic receptor response.