The goal of this study was to determine the effects of trimetazidine on all-cause mortality and heart failure hospitalizations in patients with ischemic cardiomyopathy. We performed an extension to 48 months and a post-hoc analysis of the Villa Pini d'Abruzzo trimetazidine trial; in this single-center, open-label, randomized trial with the metabolic inhibitor trimetazidine in chronic heart failure, 61 patients were randomized to either receive trimetazidine (20 mg tid) in addition to their conventional treatment or to continue their usual drug therapy for 4 years. Patients were evaluated at baseline and at 6, 12, 18, 24, 32, 36, 42, and 48 months with clinical examination, echocardiography, and 6-minute walking test. Trimetazidine added to usual treatment significantly reduces all-cause mortality (-56%; hazard ratio, 0.258; 95% CI, 0.097 to 0.687; log-rank test, P = 0.0047), heart failure hospitalization (-47%; log-rank test, P = 0.002), and improves patient functional status (NYHA class and 6-min walking test). In trimetazidine-treated patients, a significant increase of the left ventricle ejection fraction was also detected (LVEF P < 0.001 at 48 months). It is therefore concluded that long-term trimetazidine significantly reduces all-cause mortality and heart failure hospitalization in patients with ischemic cardiomyopathy. If confirmed in large-scale randomized trials, this treatment could be useful in the management of left ventricle dysfunction and remodeling in patients with ischemic heart disease.