Maternal obesity influences a number of metabolic factors that can affect the course of pregnancy. Among these factors, leptin plays an important role in energy metabolism and fetal development during pregnancy. Our objective was to estimate the influence of maternal overweight/obesity on variation in the maternal serum leptin profile during pregnancy. In a prospective cohort of 143 adult gravidas with singleton pregnancies presenting for general prenatal care, we measured serum leptin levels at 6-10, 10-14, 16-20, 22-26, and 32-36 weeks' gestation. The longitudinal effects of maternal prepregnancy BMI, categorized as nonoverweight (≤26.0kg/m2) and overweight/obese (≤26.0kg/m2), on serum leptin concentration were analyzed using linear mixed models. Overweight/obese women had significantly higher serum leptin concentrations than their nonoverweight counterparts throughout pregnancy (P 0.01). Although these concentrations increased significantly across gestation for both groups, the rate of increase was significantly smaller for overweight/obese women (P 0.05). To investigate whether these differences merely reflected differences in weight-gain patterns between the two groups, we examined an index of leptin concentration per unit body weight (leptin (ng/ml)/weight (kg)). Overweight/obese women had a significantly higher index throughout pregnancy (P 0.01). However, although this index increased significantly across pregnancy for nonoverweight women, it actually decreased significantly for overweight/obese women (P 0.01). Our results suggest that factors other than fat mass alone influence leptin concentrations in overweight/obese women compared to normal-weight women during pregnancy. Such factors may contribute to differences in the intrauterine environment and its influence on pregnancy outcomes in the two groups.