Background: Leptin has been associated with left ventricular (LV) hypertrophy and heart failure in some epidemiologic studies while other studies have demonstrated a beneficial effect on cardiac remodeling and function. We hypothesized that leptin may play a role in protecting the heart from developing LV hypertrophy and stiffening. Methods and Results: We evaluated 1172 African Americans with preserved LV ejection fraction (EF >50%) from the Genetic Epidemiology Network of Arteriopathy (GENOA) Study (mean age 62.9 years, 72% women). LV diastolic stiffness was assessed by echocardiography using the diastolic wall strain (DWS) indicator. Associations between leptin levels and indices of LV structure and function were evaluated using generalized estimating equations (GEE) approach with Gaussian distribution accounting for clustering in siblings. All models were adjusted for possible confounders including age, body mass index, systolic blood pressure, blood pressure lowering medication, coronary heart disease, current smoking status and estimated glomerular filtration rate and stratified by sex because leptin levels were three times higher in women than men (p <0.001). After adjustment, higher leptin levels were associated with lower LV mass and less LV diastolic stiffness (p <0.05, for both) in women, while there were no statistically significant associations between leptin levels and LV structure and function in men. In women, there were interactions between leptin levels and body mass index quartiles on LV mass and LV diastolic stiffness (p <0.05, for both). Higher leptin levels were associated with lower LV mass and LV diastolic stiffness more in obese rather than in lean women (Figure). Conclusions: Higher leptin levels were associated with lower LV mass and LV diastolic stiffness in obese African American women. Leptin may play an important role in protecting the heart from developing precursors to heart failure in obese African American women.