Objectives: Statins activate phosphatidylinositol-3-kinase which activates ecto-5’-nucleotidase and phosphorylates 3-phosphoinositide-dependent-kinase-1 (PDK1). P-PDK1 phosphorylates Akt which phosphorylates endothelial-nitric-oxide-synthase (eNOS). We asked if the blockade of adenosine receptors (A₁, A_2A, A_2B or A₃) could attenuate the induction of Akt and eNOS by atorvastatin (ATV), and whether ERK 1/2 is involved in ATV regulation of Akt and eNOS. Methods: Protocol 1: Mice received intraperitoneal ATV; theophylline (TH); ATV+TH; or vehicle. Protocol 2: Mice received intraperitoneal injection of ATV; U0126 (an ERK 1/2 inhibitor); ATV+U0126; or vehicle. Eight hours later the hearts were assessed by immunoblotting. Protocol 3: Mice received intraperitoneal ATV alone or with SPT. One, 3 and 6h after injection, hearts were assessed by immunoblotting. Protocol 4: Mice received intraperitoneal ATV alone or with SPT, DPCPX, CSC, alloxazine or MRS1523. Three hours after injection hearts were assessed by immunoblotting. Results: ATV increased P-ERK, P-PDK1, Ser-473-P-Akt, Thr-308-P-Akt, and P-eNOS levels. TH blocked ATV-induced increases in P-ERK, Ser-473-P-Akt, Thr308-P-Akt and P-eNOS, without affecting the induction of P-PDK1 by ATV. U0126 blocked the ATV induction of Ser-473-P-Akt and Thr-308-P-Akt while attenuating the induction of P-eNOS. A detectable increase in P-ERK, Ser-473-P-Akt and P-eNOS was seen 3 and 6h after injection, but not at 1h. DPCPX, CSC and alloxazine partially blocked the ATV induction of P-ERK, Ser-473-P-Akt and P-eNOS. Conclusion: Blockade of adenosine receptors A₁, A_2A and A_2B but not A3 inhibited the induction of Akt and eNOS by statins. Adenosine was required for ERK 1/2 activation by statins, which resulted in Akt and eNOS phosphorylation.