Background-Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Methods and Results-Forty-six consecutive patients with symptomatic exercise limitation (peak V o 2 Ͻ75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55Ϯ0.26 years) were randomized to perhexiline 100 mg (nϭ24) or placebo (nϭ22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by 31 P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak V o 2 , symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6Ϯ1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27Ϯ0.02 to 1.73Ϯ0.02 versus 1.29Ϯ0.01 to 1.23Ϯ0.01; Pϭ0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11Ϯ0.008 to Ϫ0.01Ϯ0.005 versus 0.15Ϯ0.007 to 0.11Ϯ0.008 second; Pϭ0.03). These changes were accompanied by an improvement in primary end point (peak V O 2 ) (22.2Ϯ0.2 to 24.3Ϯ0.2 versus 23.6Ϯ0.3 to 22.3Ϯ0.2 mL ⅐ kg Ϫ1 ⅐ min Ϫ1 ; Pϭ0.003) and New York Heart Association class (PϽ0.001) (all P values ANCOVA, perhexiline versus placebo). Conclusions-In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00500552.