Complete leptin deficiency is associated with weight gain and extreme obesity, according to studies of animals and of monogenic obesity in humans. It is still a matter of debate whether relative leptin deficiency plays a physiologic role in adiposity regulation in free-living humans. We hypothesized that leptin levels would be associated with subsequent weight changes in healthy normal-weight young adults. Our prospective cohort involved 150 healthy young adults (114 women and 36 men) followed over their years of study at the Université de Sherbrooke. Anthropometric measurements, fasting blood samples, 3-day food diaries, and a physical activity questionnaire were collected at baseline. Leptin levels were measured with radioimmunoassay. Associations between baseline leptin levels and subsequent anthropometric changes were assessed with multivariable linear regression models to account for adiposity at baseline, food intake, and energy expenditure. Over the 2-year follow-up, changes in body mass index (BMI) ranged from -0.8 to +2.6 kg·m(-2) in men (mean BMI change, +0.6 kg·m(-2)) and from -2.5 to +3.7 kg·m(-2) in women (mean BMI change, +0.1 kg·m(-2)). Lower leptin levels at baseline were associated with a higher risk of weight gain in women (r = -0.24; p = 0.01 for change in BMI) and in men (r = -0.27, p = 0.11), even after accounting for baseline BMI, total daily caloric intake, and energy expenditure (p = 0.02). In the subsample measured at 4 years (n = 63), baseline leptin levels were not associated with 4-year weight changes. Lower leptin levels are associated with a higher risk of weight gain over 2 years in healthy young adults.