Angiotensin receptor blockers (ARBs) reduce post-MI adverse left ventricular (LV) remodeling, improve LV function and survival when started post-myocardial infarction (MI). ARBs also reduce ventricular arrhythmias during ischemia-reperfusion injury when started pre-MI. No information exists regarding their efficacy and safety when started pre-MI and continued peri- and post-MI. We evaluated whether the ARB, Losartan improves outcome when started pre-MI, and continued peri- and post-MI. Male Wistar rats (n=502) were treated for 7 days pre-MI with Losartan high-dose, 30 mg/kg/day, or progressively increasing dose, 3mg/kg/day (increased to 10mg/kg/day 10 days and 30mg/kg/day 20 days post-MI) or no-treatment. Ambulatory systolic blood pressure and Holter monitoring were performed for 24-hours post-MI. Echocardiography was done 30-days post-MI, and LV remodeling, cardiac hemodynamics and fetal gene expression were assessed 38-days post-MI. High-dose Losartan reduced 24-hour post-MI survival compared to progressive dose and control (21.9% vs. 36.6%, 38.1%, p=0.033 and p=0.009 respectively). This was associated with greater hypotension in high dose, and no change in ventricular arrhythmias in all groups. In 24-hour post-MI survivors, the progressive dose group had reduced mortality from 24hour to 38-days (8.5% vs. 28.6% for control vs. 38.9% for high dose, p=0.032 and p=0.01 respectively). Survivors of both Losartan groups demonstrated improved LV remodeling, cardiac hemodynamics, preserved GLUT-4 and reduced cardiac fetal-gene expression. Pre-treatment with ARBs does not reduce 24-hour post-MI ventricular arrhythmias or survival, and high doses increase mortality by causing excessive hypotension. In 24-hour post-MI survivors, progressively increasing doses of Losartan have multiple beneficial effects, including improved survival.