Abstract—Oxidative stress plays an important role in the development of cardiac remodeling after myocardial infarction (MI), but the sources of oxidative stress remain unclear. We investigated the role of Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase in the development of cardiac remodeling after MI. Adult Nox2^-/- and matched wild-type (WT) mice were subjected to coronary artery ligation and studied 4 weeks later. Infarct size after MI was similar in Nox2^-/- and WT mice. Nox2^-/- mice exhibited significantly less left ventricular (LV) cavity dilatation and dysfunction after MI than WT mice (eg, echocardiographic LV end-diastolic volume: 75.7±5.8 versus 112.4±12.3 µL; ejection fraction: 41.6±3.7 versus 32.9±3.2%; both P<0.05). Similarly, in vivo LV systolic and diastolic functions were better preserved in Nox2^-/- than WT mice (eg, LV dP/dt_max: 7969±385 versus 5746±234 mm Hg/s; LV end-diastolic pressure: 12.2±1.3 versus 18.0±1.8 mm Hg; both P<0.05). Nox2^-/- mice exhibited less cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis; reduced increases in expression of connective tissue growth factor and procollagen 1 mRNA; and smaller increases in myocardial matrix metalloproteinase–2 activity than WT mice. These data suggest that the Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase contributes significantly to the processes underlying adverse cardiac remodeling and contractile dysfunction post-MI.