Background-Oxidative stress plays an important role in the pathophysiology of heart failure. We determined whether the overexpression of glutathione peroxidase (GSHPx) could attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI). Methods and Results-We created MI in 12-to 16-week-old, male GSHPx transgenic mice (TGϩMI) and nontransgenic wild-type littermates (WTϩMI) by ligating the left coronary artery. GSHPx activity was increased in the hearts of TG mice, with no significant changes in other antioxidant enzymes. LV concentrations of thiobarbituric acid-reactive substances measured in TGϩMI at 4 weeks were significantly lower than those in WTϩMI. The survival rate during 4 weeks of MI was significantly higher in TGϩMI than in WTϩMI, although the infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in TGϩMI. LV end-diastolic pressure was increased in WTϩMI and reduced in TGϩMI. Improvement of LV function in TGϩMI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis in the noninfarcted LV. Myocardial matrix metalloproteinase-9 zymographic and protein levels were increased in WTϩMI after 3 days but were attenuated in TGϩMI. Conclusions-Overexpression of GSHPx inhibited LV remodeling and failure after MI. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac failure.