Introduction: Newborn rats exhibit natural heart regeneration after myocardial infarction (MI), yielding no evidence of cardiac dysfunction or scar at 3 weeks post-MI. This phenotype is absent when MI occurs after 1 week of age. The long-term function of the regenerated heart and its impact on survival post-MI have not been studied. We hypothesized that natural heart regeneration preserves cardiac function and normalizes survival through adulthood. Methods: Wistar rat neonates (n=51) underwent left anterior descending coronary artery ligation on postnatal day 1 (P1, n=17) or postnatal day 9 (P9, n=12). Sham surgery was performed in littermates (P1 n=12, P9 n=10). The rats were observed for the entirety of their lifespan, reaching 18 months post-MI (equivalent to 45 human years) at the time of this analysis. Echocardiography was obtained at 15 months post-MI. After each mortality event, hearts were sectioned and stained with Masson’s trichome. Results: Echocardiography at 15 months after P1 MI vs P1 sham surgery revealed no differences in left ventricular (LV) wall thickness (p=0.881, Fig 1A) or end-diastolic diameter (p=0.118, Fig 1B), and LV ejection fraction (EF) was sustained within normal limits (63.2% vs 68.5%, p=0.003, Fig 1C). In contrast, after P9 MI, severe LV wall thinning (p<0.001), massive LV dilation (p<0.001), and profoundly depressed EF were observed (41.8% vs 69.1%, p<0.001). Concordant results were observed for both sexes. Trace scar was detected after P1 MI, while large infarcts and LV aneurysms were observed after P9 MI (Fig 1D). At 18 months post-MI, overall survival was 13/17 (76.5%) in the P1 MI group compared to 9/12 (75.0%) in the P1 sham group (p>0.999) and 3/12 (25.0%) in the P9 MI group (p=0.009). Conclusions: Natural heart regeneration mechanisms may offer long-term protection from LV dysfunction and mortality after cardiac injury, suggesting potential applications in congenital heart surgery and as a durable treatment for ischemic cardiomyopathy.