Objectives. This study compared the effects of rosuvastatin on left ventricular infarct size in mice following permanent coronary occlusion versus 60 minutes ischemia/24 hours reperfusion and evaluated the effects of rosuvastatin on potential beneficial mechanisms of infarct size reduction including neutrophil accumulation, NO synthase expression and stem cell mobilization following ischemia and reperfusion. Background. Statins can inhibit neutrophil adhesion, increase NO synthase expression and mobilize progenitor stem cells following ischemic injury. Methods. Mice received blinded and randomized administration of 20 mg/kg/day rosuvastatin or saline 2 days before surgery until sacrifice. In 60 minutes ischemia/reperfused mice, neutrophils were counted in injured myocardium, circulating CD34+, Sca-1+ and c-kit+ cells were measured, and left ventricular NOS3 mRNA and protein levels were determined. The effect of rosuvastatin on infarct size after permanent LAD occlusion was also determined in NOS3 deficient mice. Results. Following 60 minutes ischemia with reperfusion, infarct size was reduced by 18% (p=0.03) in mice randomized to receive rosuvastatin (n=18) vs. saline (n=22) but was similar following permanent occlusion in rosuvastatin (n=17) vs. saline (n=20)groups (p=NS). In NOS3 deficient mice, myocardial infarct size after permanent LAD occlusion (N=6) tended to be greater than that in the wild type saline group (33+4 vs. 23+2%, p=0.08). However, infarct size in NOS3 deficient mice was not modified by treatment with rosuvastatin (34+5%, N=6, p=NS vs. NOS3 deficient saline group). After 60 minutes ischemia/reperfusion, neutrophil infiltration was similar between rosuvastatin and saline groups (465+131 vs. 527+136 neutrophils/section, p=NS) as was the percentage of CD34+ (3.7+1.0 vs. 6.4+2.0 %, P=NS), Sca-1+ (4.0+1.0 vs. 6.2+1.2 %, P=NS) and c-Kit+ (5.1+1.4 vs. 6.4+1.4 %, P=NS) cells. Left ventricular NOS3 mRNA and protein levels were unchanged by rosuvastatin. Conclusions. Rosuvastatin reduces infarct size following 60 minutes ischemia/reperfusion but not following permanent coronary occlusion, suggesting a potential anti-inflammatory effect. Although we were unable to demonstrate that the myocardial protection was due to an effect on neutrophil infiltration, stem cell mobilization or induction of NOS3, these data suggest that rosuvastatin may be particularly beneficial in myocardial protection following ischemia-reperfusion injury.