Objectives: We assessed whether aspirin (ASA), administered before reperfusion, abrogates the infarct size (IS) limiting effect of atorvastatin (ATV). Statins reduce infarct size (IS). This dose-dependent effect is mediated by upregulation of cycloxygenase-2 (COX2) and PGI₂ production. Administration of selective COX2-inhibitors either with ATV for 3 days or immediately before coronary occlusion blocks the IS-limiting effect of ATV. Methods: Sprague-Dawley rats received 3-day ATV (10mg/kg/d) or water alone. Rats underwent 30min coronary artery occlusion and 4h reperfusion (IS protocol, n=8 in each group) or rat underwent 30min coronary artery occlusion and 10 min reperfusion (enzyme expression and activity protocol, n=4 in each group). Immediately before reperfusion rats received intravenous ASA (5, 10, or 20 mg/kg) or saline. Area at risk (AR) was assessed by blue dye and IS by triphenyl-tetrazolium-chloride. Results: ATV reduced IS (10.1±1.4% of the area at risk) compared with controls (31.0±2.2%). Intravenous ASA alone did not affect IS (29.0±2.6%); however, ASA dose-dependently (5, 10 and 20 mg/kg) attenuated the protective effect of ATV on IS (15.8±0.9%, 22.0±1.6%, and 23.7±3.8%, respectively). ASA dose-dependently blocked the upregulation of COX2 by ATV. COX2 activity was as follows: control: 8.93±0.90 pg/mg; ATV: 75.85±1.08 pg/mg; ATV+ASA5: 34.39±1.48 pg/mg; ATV+ASA10: 19.87±1.10 pg/mg; and ATV+ASA20: 9.36±0.94 pg/mg. Conclusions: ASA, administered before reperfusion in doses comparable to those used in the clinical setting, abrogates the IS-limiting effect of ATV in a model with mechanical occlusion of the coronary artery. This potential adverse interaction should be further investigated in the clinical setting of acute coronary syndromes.