Peripheral blood mononuclear cells of chronic heart failure (CHF) patients produce great amounts of pro-inflammatory cytokines, indicating that circulating cells are activated and could mirror changes occurring in inflammatory cells infiltrating the failing heart. Adenosine is a regulatory metabolite acting through four membrane receptors that are linked to adenylyl cyclase: activation of the A(2A) receptor subtype has been reported to inhibit cytokine release. Changes of the adenosinergic system may play a role in CHF development. Here we report an increase of A(2A) receptor expression, density, and coupling to adenylyl cyclase in blood circulating cells of CHF patients. A(2A) receptor up-regulation was also found in the explanted hearts of these patients, suggesting that changes of peripheral adenosine receptors mirror changes occurring in the disease target organ. In a cohort of patients followed longitudinally after heart transplantation, alterations of peripheral A(2A) adenosine receptor progressively normalized to control values within 6 months, suggesting that improvement of cardiac performance is accompanied by progressive restoration of a normal adenosinergic system. These results validate the importance of the A(2A) receptor in human diseases characterized by a marked inflammatory/immune component and suggest that the evaluation of this receptor in peripheral blood cells may be useful for monitoring hemodynamic changes and the efficacy of pharmacological and non-pharmacological treatments in CHF patients.