Inhibition of mitochondrial permeability transition pore (mPTP) opening by cyclosporin A or ischemic postconditioning attenuates lethal reperfusion injury. Its impact on major post-myocardial infarction events, including worsening of left ventricle (LV) function and death, remains unknown. We sought to determine whether pharmacological or postconditioning-induced inhibition of mPTP opening might improve functional recovery and survival following myocardial infarction in mice. Anesthetized mice underwent 25 minutes of ischemia and 24 hrs (protocol 1) or 30 days of reperfusion (protocol 2). At reperfusion, they received either no intervention (control), postconditioning (3 cycles of 1 minute ischemia / 1 minute reperfusion) or intravenous (IV) injection of the mPTP inhibitor Debio-025 (10 mg/kg). At 24 hour of reperfusion, mitochondria were isolated from risk region for assessment of the calcium retention capacity (CRC). Infarct size was measured by TTC staining. At 30 days of reperfusion, mortality and LV contractile function (echocardiography) were evaluated. Postconditioning and Debio-025 significantly improved CRC (132±13 and 153±31 versus 53±16 nmoles Ca²⁺/mg prot in control), and reduced infarct size to 35±4 and 32±7 % of risk area versus 61±6 % in control (p<0.05). At 30 days, ejection fraction averaged 74±6% and 77±6% in postconditioned and Debio-025, respectively versus 62±12 % in control (p<0.05). At 30 days, survival was improved from 58% in control to 92% and 89% in postconditioned and Debio-025 groups, respectively. Inhibition of mitochondrial permeability transition at reperfusion improves functional recovery and mortality in mice.