Liver X receptors, LXRα (NR1H3) and LXRβ (NR1H2), are best known as nuclear oxysterol receptors and physiological master regulators of lipid and cholesterol metabolism. LXRα play a protective role in acute myocardial ischemia/reperfusion (MI/R) injury, but its role in myocardial infarction (MI) is unknown. The present study was undertaken to determine the effect of LXRα knockout on survival and development of chronic heart failure after MI. Wild-type (WT) and LXRα^−/− mice were subjected to MI followed by serial echocardiographic and histological assessments. Greater myocyte apoptosis and inflammation within the infarcted zones were found in LXRα^−/− group at 3 days after MI. At 4 weeks post-MI, LXRα^−/− MI murine hearts demonstrated significantly increased infarct size, reduced ejection fraction (LXRα^−/− 29.4 % versus WT 34.4 %), aggravated left ventricular (LV) chamber dilation, enhanced fibrosis and reduced angiogenesis. In addition, LXRα^−/− mice had increased mortality compared with WT mice. LXRα deficiency increases mortality, aggravates pathological injury and LV remodeling induced by MI. Drugs specifically targeting LXRα may be promising in the treatment of MI.