Increasing adiposity increases the risk for left ventricular (LV) hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data were obtained from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor-α, and resistin). One-thousand four hundred sixty four MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m², and 49% were women. With adjustment for age, gender, race, height, and weight, multivariate linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (ß: −4.66% predicted, p <0.01), LV volume (−5.87% predicted, p <0.01), stroke volume (−3.23 ml, p <0.01), and cardiac output (−120 ml/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (odds ratio 0.65, p <0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines, and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely nonsignificant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function.