Adenosine receptors have been described in brain, bone, and platelets. Stimulation of this receptor by adenosine results in increased adenyl cyclase activity and accumulation of cyclic AMP. We have identified an adenosine receptor on human peripheral lymphocytes. Adenosine (5-100 μM) increased lymphocyte cyclic AMP levels by 100% during a 5-min incubation. Adenine was without stimulatory effect. Theophylline, which did not alter cyclic AMP levels when added alone, reduced the effect of added adenosine by 33% during a 5-min incubation. Norepinephrine alone elevated cyclic AMP levels 500-900% and the effects of adenosine and norepinephrine were additive. These data fulfill the criteria for the demonstration of a specific adenosine receptor. T lymphocytes isolated from a patient with x-linked agammaglobulinemia also demonstrated the presence of the adenosine receptor linked to cyclic AMP accumulation. Persistently elevated levels of cyclic AMP inhibit both lymphocyte proliferation and antibody synthesis. Patients with adenosine deaminase deficiency and severe combined immunodeficiency have markedly impaired lymphocyte proliferation and antibody production. These patients have also been found to have an increased intracellular concentration of ATP and elevated levels of plasma adenosine. Theophylline (0.5 mM), which decreases cyclic AMP breakdown by inhibiting phosphodiesterase, inhibited normal lymphocyte proliferation by 50%. In contrast, the same concentration of theophylline inhibited adenosine deaminase-deficient lymphocyte proliferation by 89%. These data suggest that the immunologic defects in severe combined immunodeficiency and adenosine deaminase deficiency may result in part from excessive cyclic AMP synthesis associated with overstimulation of the adenosine receptor-adenyl cyclase pathway.