Many human diseases result from the influence of the nutritional environment on gene expression. The environment interacts with the genome by altering the epigenome, including covalent modification of nucleosomal histones. Here, we report a novel and dramatic influence of diet on the phenotype and survival of mice in which histone deacetylase 3 (Hdac3) is deleted postnatally in heart and skeletal muscle. Although embryonic deletion of myocardial Hdac3 causes major cardiomyopathy that reduces survival, we found that excision of Hdac3 in heart and muscle later in development leads to a much milder phenotype and does not reduce survival when mice are fed normal chow. Remarkably, upon switching to a high fat diet, the mice begin to die within weeks and display signs of severe hypertrophic cardiomyopathy and heart failure. Down-regulation of myocardial mitochondrial bioenergetic genes, specifically those involved in lipid metabolism, precedes the full development of cardiomyopathy, suggesting that HDAC3 is important in maintaining proper mitochondrial function. These data suggest that loss of the epigenomic modifier HDAC3 causes dietary lethality by compromising the ability of cardiac mitochondria to respond to changes of nutritional environment. In addition, this study provides a mouse model for diet-inducible heart failure.