After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, 1 H MRI and 31 P magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P Ͻ 0.005), and the LV ejection fraction (EF) decreased (14 Ϯ 9%) compared with control hearts (59 Ϯ 8%, P Ͻ 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 Ϯ 0.6) compared with control animals (2.1 Ϯ 0.5, P Ͻ 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 Ϯ 9%, P ϭ 0.01), and normalized cardiac PCr/ATP (2.0 Ϯ 0.5, P Ͻ 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction. postinfarction remodeled myocardium; cardiac metabolism; magnetic resonance spectroscopy; allopurinol VENTRICULAR REMODELING occurs after myocardial infarction (MI) in many species, including humans, and is typically characterized by progressive ventricular dilatation, eccentric hypertrophy, and contractile dysfunction (27,36,38). Patients with post-MI remodeling experience increased rates of heart failure and cardiovascular mortality, whereas interventions that reduce geometric ventricular remodeling improve outcomes (27,40,41,44). In addition to the geometric and contractile abnormalities associated with post-MI remodeling, adverse changes in energy metabolism also occur (15,29,32). Abnormalities in energy metabolism after MI include reductions in ATP, phosphocreatine (PCr), and in the activity of the creatine kinase (CK) reaction, the primary energy reserve reaction of the heart (20, 21, 29, 31). Inhibitors of CK significantly increase mortality after experimental infarction (16). The reduction in cardiac PCr-to-ATP ratio (PCr/ATP) in experimental postinfarction remodeling is similar to that observed in human heart failure, which, in turn, correlates with clinical severity and predicts overall and cardiovascular mortality (4,10,15, 31,34,49). Taken together, the ene...