Background: Sildenafil, a phosphodiesterase type 5 inhibitor, has recently been shown to induce cardioprotection against myocardial ischemia/reperfusion injury. Objective: We investigated whether sildenafil could limit infarct expansion in a porcine model of acute myocardial infarction (MI). Methods: 24 female pigs (20-25 kg) were assigned to 4 groups: group 1, control (n=6); group 2, perindopril 2 mg (n=6); group 3, sildenafil 50 mg (n=6); and group 4, perindopril 2 mg and sildenafil 50 mg daily (n=6). The study medications were administered within 24 hours after induction of acute MI by occlusion of the left anterior descending artery for 40 minutes. All subjects underwent MDCT scan at 3-5 days and 30 days after the procedure. Infarct size was determined as the ratio of the area showing delayed enhancement to the total LV myocardial area and infarct size reduction as change between two MDCT measurements. Results: Infarct size, infarct wall thickness, and left ventricular ejection fraction (LVEF) at day 3-5 and day 30 were similar across the experimental groups. Infarct size measured by MDCT was well correlated with that estimated by 2,3,5-triphenyl tetrazolium chloride staining. Changes in infarct wall thickness and LVEF were similar between the groups. Quantitative assessment of temporal infarct expansion showed, however, incremental differences between the groups (-7.7짹5.1%, -13.8짹8.2%, -15.3짹8.3%, -17.8짹5.0, p=0.086) with significant infarct size reduction in group 4, compared to group 1 (p=0.032). Conclusion: Sildenafil in conjunction with an ACE inhibitor was effective in limiting post-MI LV remodeling by reducing infarct expansion.