Aging is a risk factor for coronary and peripheral artery disease. The role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in post-acute myocardial infarction (post-AMI) recovery is not well understood. We hypothesized that TNF signaling through its receptors p55 and p75 may be essential in post-AMI regeneration in adult heart. To test our hypothesis we evaluated post-AMI survival, cardiac function, apoptosis, and angiogenesis in AMI model (LAD ligation) in age-matched young (4-8 weeks old) and old (9-14 months old) WT, p75KO, and p55KO mice. In old WTs there was significant fourfold age-associated increase in post-AMI mortality. In young p75KOs post-AMI mortality was approaching mortality in old WTs (35% vs. 45%) whereas >1/2 of old p75KOs (60%) died within 7 days post-AMI. No post-AMI mortality was observed in young p55KOs, and in old p55KOs post-AMI mortality was lower than in young WTs (10% vs. 15%). Compared to young WT, between days 7 and 28 post-AMI functional recovery (% left ventricular (LV) fractional shortening (FS)) was 10% lower in old WTs and young p75KOs (p<0.05) and more than 20% lower in old p75KOs (p<0.05). In contrast, 28 days after post-AMI in young p55 % LV FS was back to pre-AMI levels and in old p55KO post-AMI LV FS was as good as in young WTs. Since mice of p75KO genotype revealed the worst post-AMI recovery we concentrated our histopathologic studies in young and old p75KO mice. To evaluate ongoing MI injury, we immunostained hearts with cardiac troponin I (cTnI). Compared to non-infarct tissue, cTnI expression was significantly increased in infarct border zone of young p75KOs, old WTs, and old p75KOs 7 days post-AMI, and cTnI was the highest in old p75KOs, indicating significant amplification of myocardial damage in old p75KOs. In addition, compared to young WTs there was significant decrease in capillary density (BS1-lectin staining) and the number of functional vessels (BS1-lectin perfusion) in old WT and young p75KOs in infarct/infarct border zone. There was further threefold post-AMI decrease (p<0.001) in functional vessels in old p75KOs compared to old WTs. To corroborate our findings to human condition peripheral blood (PB) endothelial progenitor cells (EPCs) from young volunteers (32±14 years old) and adult CAT lab patients (62±7 years old) were evaluated for expression of angiogenic (VEGF-A, ANG-2, TGF-β, HIF-1α, ET-1), stromal cell-derived factor and their receptors (SDF-1α, CXCR4, and GCSFR) by qRT-PCR. There was significant 2-5-fold (p<0.02) decreases in the gene expression of these factors in EPCs from adult patients. Our results strongly suggest critical role of TNF signaling through its receptors p55 and p75 in the processes of post-ischemic recovery in adult tissue after myocardial infarction, that is, signaling via TNFR1/p55 is deleterious, whereas signaling via TNFR2/p75 is protective in repair and regeneration processes in adult infarct myocardium.