Abstract: AIM:To evaluate the effects and mechanisms of cyclosporin A (CsA) in protecting against myocardial ischemia/reperfusion injury in a swine model. METHODS: Models were established by coronary angioplasty percutaneous balloon occlusion of the left anterior descending artery (LAD). Swine that survived after myocardial ischemia/reperfusion were divided into three groups: control (n=4), CsA (n=6) and FK-506 (n=6). The three groups received, respectively, saline vehicle 100 ml, 25 mg/kg CsA and 1 mg/kg FK-506. All animals underwent 90 min of regional ischemia and 3 h of reperfusion. Myocardial infarct size and apoptotic cell death were determined by pathological assessment and immunohistopathology. Transmission electron microscopy was used to evaluate morphologic differences in the mitochondria between the groups. RESULTS: Infarct size in CsA group was significantly reduced compared with that in control group ［(7.5±0.6) cm2 vs.(10.5±2.6) cm2, P<0.01］ and FK-506 group ［(7.5±0.6) cm2 vs.(9.6±2.7) cm2, P<0.019］. Apoptotic index in CsA group was also attenuated compared with that in control group ［(11.9±1.88)% vs.(22.3±1.66)%, P<0.01］ and FK-506 group ［(11.9±1.88)% vs.(19.2±1.82)%, P<0.01］. Transmission electron microscopy revealed a preservation of normal mitochondrial morphology and a reduction in the percentage of disrupted mitochondria in CsA group (20%±7%) compared with those in control group (53%±12%) and FK-506 group (47%±9%). CONCLUSION: Cyclosporine A-induced mPTP inhibition preserves mitochondrial morphology after myocardial ischemia/reperfusion and limits myocyte necrosis and apoptosis. These effects are independent of calcineurin inhibition.