Here we demonstrate that in human umbilical vein ECs (HUVECs), A_2AAR expression constitutively suppressed tyrosine phosphorylation of STATs 1 and 3 in response to either an interleukin-6 (IL-6) trans-signalling complex or interferon-α by priming them for cytokine-triggered degradation by the proteasome. This did not simply reflect a negative effect of A_2AAR expression on HUVEC viability compared to controls, as determined by MTT assays. Moreover, several lines of evidence argued that the cytokine dependence of the effect reflected a requirement for JAK-mediated phosphorylation of STATs. First, pre-treatment with JAK inhibitor prevented down-regulation. Second, the ability of leptin to specifically promote the tyrosine phosphorylation of STAT3 and not STAT1 was reflected in the preferential down-regulation of STAT3 induced by leptin in A_2AAR-expressing cells. Third, a Y705F-mutated STAT3 was resistant to down-regulation by cytokine in A_2AAR-expressing cells. Finally, immunoprecipitation of endogenous and recombinant STATs revealed that cytokine treatment triggered the accumulation of polyubiquitylated STATs in A_2AAR-expressing cells, and that this effect was abolished by Y705F mutation. Together, these observations identify a previously unappreciated mechanism by which a cyclic AMP-mobilising G-protein-coupled receptor can negatively regulate cytokine receptor signalling in the endothelium.