Recent studies suggest that statin therapy reduces hospitalizations for heart failure (HF). However, few data exist regarding the role of statins in preventing HF after acute myocardial infarction (AMI). In addition, the potential impact of left ventricular (LV) ejection fraction (EF) and coexisting functional mitral regurgitation (MR) on the efficacy of statin therapy was not considered. We prospectively studied 1,563 patients with AMI. The primary endpoint was readmission for the treatment of HF. The effect of statin therapy initiated before hospital discharge was evaluated using a Cox model, adjusting for clinical variables, a propensity score for statin therapy, LVEF, and MR grade. Patients with recurrent infarctions were censored. Statins were prescribed in 1,048 patients (67.1%) before hospital discharge. During a median follow-up of 17 months, admissions for HF were lower in patients receiving statins (6.5% vs 14.8%; unadjusted hazard ratio 0.45, 95% confidence interval 0.32 to 0.63, p <0.0001). In a multivariable Cox model, statin therapy was associated with a significant reduction of hospitalization for HF (HR 0.62, 95% confidence interval 0.43 to 0.89, p = 0.009). There was a significant interaction between MR and statin therapy (p = 0.039), such that the beneficial effect of statins on HF hospitalizations was most pronounced in patients without concomitant MR and absent in patients with hemodynamically significant MR. In conclusion, in patients with AMI statin therapy initiated before hospital discharge significantly reduces subsequent hospitalizations for HF. The effect of statins is driven largely by the reduction in events in patients without concomitant hemodynamically significant MR.