NF-B is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-B ameliorate cardiac remodeling and failure after myocardial infarction (MI). Knock-out mice with targeted disruption of the p50 subunit of NF-B (KO) were used to block the activation of NF-B. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-B was activated in non-infarct as well as infarct myocardium in WT+MI mice, while the activity was completely abolished in KO mice. Blockade of NF-B significantly reduced early ventricular rupture after MI and improved the survival by ameliorating congestive heart failure. Echocardiographic and pressure measurement revealed that left ventricular fractional shortening and + dP/dt_max were significantly increased and end-diastolic pressure was significantly decreased in KO+MI mice compared to WT+MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in non-infarct myocardium in KO+MI mice. Blockade of NF-B did not ameliorate expression of proinflammatory cytokines in infarct or non-infarct myocardium. In contrast, phosphorylation of c-Jun N-terminal kinase was almost completely abolished in KO+MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-B reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-B might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.