Osteoprotegerin, a member of the tumor necrosis factor receptor superfamily, has pleiotropic effects on bone metabolism, endocrine function, and the immune system. Myocardial expression and circulating levels of osteoprotegerin are increased in heart failure. The relationship between osteoprotegerin levels in the general population and indices of left ventricular structure and function is unknown. Plasma osteoprotegerin levels and cardiac MRI indices of left ventricular structure and function were available in 2715 subjects (median age: 44 years; 45% male) enrolled in the Dallas Heart Study. The associations between osteoprotegerin concentration and indices of left ventricular structure and function were assessed by linear regression analysis, adjusting for possible confounders. By gender-specific linear regression analysis, higher osteoprotegerin levels were significantly associated with higher left ventricular mass, left ventricular wall thickness, left ventricular concentricity index, and lower left ventricular ejection fraction (P<0.001 for all). After adjustment for age, race, fat-free mass, fat mass, hypertension, diabetes, coronary artery disease, estimated glomerular filtration rate, hypercholesterolemia, smoking status, hormone replacement therapy, coronary artery calcium score >10, and presence of aortic plaque, osteoprotegerin remained significantly associated with each of these left ventricular indices among male subjects (P<0.05 for each). Among female subjects, higher osteoprotegerin was independently associated with higher left ventricular end-systolic volume and lower ejection fraction (P<0.0001 for each) but not with indices of left ventricular hypertrophy. These findings are compatible with the theory that osteoprotegerin may play a pathophysiological role in the development of left ventricular hypertrophy and systolic dysfunction.