Recent studies have shown that the decrease in ventricular septal rupture (VSR) incidence after acute myocardial infarction is related to the improvement of reperfusion strategies. Our main objective was to explore the influence of therapeutic management changes on post-infarct VSR patient outcomes in a single reference center over a period of 30 years. We analyzed therapeutic management strategies and mortality rates in 228 patients with VSR after acute myocardial infarction admitted from 1981 to 2010. Patients were classified in 3 successive decades. There were no significant differences in clinical characteristics of patients with VSR at admission among those decades. Overall, surgery was performed in 159 patients (71.9%), primary transcatheter VSR closure was attempted in 5 patients (2.2%), and 64 patients (27.6%) were managed medically. Independent predictors of in-hospital mortality were VSR surgical repair (odds ratio [OR] 0.22, 95% confidence interval [CI] 0.1 to 0.7, p = 0.008), cardiogenic shock (OR 6.06, 95% CI 2.8 to 13.1, p <0.0001), and Killip class on admission (OR 1.75, 95% CI 1.1 to 9.9, p = 0.02). We found a significant 1-year mortality reduction between the first and second decades (hazard ratio 0.48, 95% CI 0.28 to 0.80; p = 0.005), with no significant change in the last decade (p = 0.2). This change was related to a systematic referral to surgical repair and shorter delays to VSR surgery (5.2 ± 6.3 vs 1.9 ± 3.2 days from first to second decade; p = 0.012). In conclusion, surgical repair remains the only significant efficient therapy to reduce mortality in patients with VSR (p <10⁻³). In-hospital prognosis remains disappointing. This contrasts with the favorable long-term outcome of patients who survive the perioperative period and are discharged from hospital.