OBJECTIVE: To explore cross-sectional associations between short sleep duration and variations in body fat indices and leptin levels during adulthood in a sample of men and women involved in the Québec Family Study. RESEARCH METHODS AND PROCEDURES: Anthropometric measurements, plasma lipid-lipoprotein profile, plasma leptin concentrations, and total sleep duration were determined in a sample of 323 men and 417 women ages 21 to 64 years. RESULTS: When compared with adults reporting 7 to 8 hours of sleep per day, the adjusted odds ratio for overweight/obesity was 1.38 (95% confidence interval, 0.89 to 2.10) for those with 9 to 10 hours of sleep and 1.69 (95% confidence interval, 1.15 to 2.39) for those with 5 to 6 hours of sleep, after adjustment for age, sex, and physical activity level. In each sex, we observed lower adiposity indices in the 7- to 8-hour sleeping group than in the 5- to 6-hour sleeping group. However, all of these significant differences disappeared after statistical adjustment for plasma leptin levels. Finally, the well-documented regression of plasma leptin levels over body fat mass was used to predict leptin levels of short-duration sleepers (5 and 6 hours of sleep), which were then compared with their measured values. As expected, the measured leptin values were significantly lower than predicted values. DISCUSSION: There may be optimal sleeping hours at which body weight regulation is facilitated. Indeed, short sleep duration predicts an increased risk of being overweight/obese in adults and is related to a reduced circulating leptin level relative to what is predicted by fat mass. Because sleep duration is a potentially modifiable risk factor, these findings might have important clinical implications for the prevention and treatment of obesity.