Background: Ischemic mitral regurgitation (IMR) portends a poor prognosis during long-term follow-up and has been identified as an independent predictor of heart failure (HF) and reduced long-term survival. Renin-angiotensin system inhibitors (RASI) including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) may improve prognosis in patients with IMR after acute myocardial infarction (AMI). The purpose of this study was to investigate the association of RASI with the incidence of adverse cardiac events in patients with IMR after AMI. Methods: We screened 867 consecutive patients admitted for AMI and underwent emergency coronary angiography between January 2000 and December 2008. A total of 388 patients who were diagnosed to have mild or greater MR evaluated by transthoracic echocardiography within 2 weeks after the onset were enrolled. Results: The mean age was 67±11 years and 297 patients (77%) were men. A total of 297 patients (77%) received RASI before hospital discharge. Patients without RASI were older and more likely to have higher creatinine level compared with patients with RASI. Left ventricular ejection fraction, peak CPK level, prevalence of prior MI were comparable between the two groups. The mean follow-up period was 5.4±3.4 years. During the follow-up, 22 cardiac deaths and 39 HF events occurred. Kaplan-Meier analysis revealed that freedom from cardiac death and HF was significantly higher in patients with RASI than in those without RASI (p<0.001 and p=0.001, respectively). After adjustment with the inverse probability treatment weighting, Cox regression analysis showed a significant beneficial effect of RASI therapy in reducing cardiac death (hazard ratio [HR]: 0.20; p<0.001) and HF (HR: 0.41; p=0.008). Conclusions: RASI was associated with a lower incidence of adverse cardiac events in patients with IMR after AMI.