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Objective. To investigate A1, A2A, A2B and A3 adenosine receptors in lymphocytes and neutrophils from early rheumatoid arthritis (RA) patients untreated and after MTX or anti TNF-a treatment compared with age-matched healthy controls. To evaluate the correlation between the status and functionality of adenosine receptors, TNF-a release and NFkB activation. Methods. Adenosine receptors were analyzed by saturation binding assays and western blotting analysis. The potency of typical A2A and A3 agonists in cAMP production of control subjects, early RA untreated and treated with MTX or anti TNF-a drugs was investigated. In a cohort of RA patients, the TNF-a release and NFkB activation were evaluated in plasma and in nuclear extracts, respectively. Results. In early RA patients high density and altered functionality of A2A and A3 receptors were present. Binding and functional parameters of A2A and A3 receptors normalized after anti TNF-a but not with MTX treatment. TNF-a release was increased in RA or MTX-treated patients but in anti TNF-a RA patients was comparable to controls. NFkB activation was elevated in untreated RA patients and after MTX treatment. Anti TNF-a treatment mediated decreased levels of NFkB activation. Conclusion. A2A and A3 receptor upregulation in RA patients and after MTX treatment was associated with high levels of TNF-a and NFkB activation. Anti TNF-a treatment normalized A2A and A3 receptor expression and functionality. These data could suggest novel therapy for the treatment of RA based on the activation of A2A and/or A3 adenosine receptors.