The A_2AAR is a critical non-redundant suppressor of inflammatory responses in vivo. While the receptor is known to elevate cyclic AMP, the molecular mechanisms underlying its anti-inflammatory effects remain obscure. To address this, we have assessed activation of the NF-κB and JAK-STAT pathways in aortas isolated from control and A_2AAR^-/- mice following treatment with or without LPS in vivo. While circulating cytokine levels were undetectable in vehicle-treated WT and A_2AAR^-/- animals, LPS-treated A_2AAR^-/- animals displayed significantly elevated levels of IL-1, IL-6, TNFα and GM-CSF compared with LPS-treated controls, consistent with a suppressive effect of A_2AAR expression on inflammatory responses. Interestingly, levels of total and IKK-phosphorylated IκBα in isolated aortic extracts were significantly elevated in vehicle- and LPS-treated mice compared with WT animals, while total levels of RelA were unaffected. In addition, levels of tyrosine phosphorylated STAT1 and STAT3 were significantly elevated in aortic extracts from LPS-treated A_2AAR^-/- versus LPS-treated WT animals while total levels of each transcription factor remained unchanged. Together, these data suggest that major roles of the A_2AAR in vivo are to A) suppress NF-κB pathway activation at the level of IKK-mediated phosphorylation of IκB and B) limit activation of the JAK-STAT pathway by restricting cytokine-triggered tyrosine phosphorylation of STATs.