The expression of myocardial fatty acid β-oxidation enzymes is downregulated at the gene transcriptional level in animal models of left ventricular hypertrophy and of heart failure. Humans with idiopathic dilated cardiomyopathy have decreased myocardial fatty acid oxidation. The extent to which molecular mechanisms, such as a reduction in myocardial fatty acid oxidation, regulate the cardiac hypertrophic response in humans in vivo is unknown. Positron emission tomography was used to measure myocardial blood flow, oxygen consumption, fatty acid utilization, and oxidation in two groups of patients: (1) hypertensive left ventricular hypertrophy (n=19; left ventricular mass, 211±39 g; left ventricular ejection fraction, 67±4%) and (2) left ventricular dysfunction (n=9; left ventricular mass, 210±36 g; left ventricular ejection fraction, 31±10%); these were compared with a normal control group (n=36; left ventricular mass, 139±25 g; left ventricular ejection fraction, 66±6%). Left ventricular mass showed significant correlation with gender, diastolic and systolic blood pressure, myocardial fatty acid uptake, utilization and oxidation, myocardial blood flow, body mass index, and left ventricular ejection fraction (all P<0.02). Independent predictors of increased left ventricular mass were male gender (r=0.38, P<0.001), myocardial fatty acid oxidation (r=−0.24, P<0.018), systolic blood pressure (r=0.41, P<0.001), and left ventricular ejection fraction (r=−0.29, P=0.005). Thus, myocardial fatty acid metabolism is an independent predictor of left ventricular mass in hypertension and in left ventricular dysfunction. The extent to which reduced myocardial fatty acid metabolism affects cardiovascular morbidity and mortality and whether pharmacologic modulation results in improved outcomes remains to be determined.