Left ventricular (LV) function post-myocardial infarction (MI) is adversely influenced by hypercholesterolemia independent of the severity of coronary atherosclerosis. The objective of this study was to evaluate whether lipid lowering by adenoviral low-density lipoprotein (LDL) receptor (AdLDLr) gene transfer in C57BL/6 LDL receptor (LDLr)-deficient mice beneficially affects ventricular remodeling and cardiac function post-MI independent of effects on the coronary circulation. AdLDLr transfer reduced plasma cholesterol by 77% (P<0.0001). Survival 28 days post-MI was higher in AdLDLr-treated mice (95%) compared with control mice (80%) (P<0.05) (hazard ratio for mortality 0.26, 95% confidence interval 0.11-0.84). Infarct size was not significantly different at day 1 and day 7 but was reduced by 18% (P<0.05) at day 28 in AdLDLr MI mice compared with control MI mice. Cardiomyocyte hypertrophy and interstitial fibrosis were reduced and neovascularization was increased in AdLDLr MI mice. LDLr gene transfer had beneficial effects on endothelial progenitor cell (EPC) number and ex vivo EPC function. LV contractility and relaxation were better preserved in AdLDLr MI mice compared with control MI mice. In conclusion, lipid lowering in hypercholesterolemic mice exerts direct cardioprotective effects resulting in enhanced survival, reduced infarct size, decreased ventricular remodeling and better cardiac function.