Gallstones are strongly associated with higher parity in women. This study prospectively assessed the incidence, natural history, and risk factors for biliary sludge and stones during pregnancy and the postpartum in 3,254 women at an army medical center. Women with a prior cholecystectomy or with stones at their first study ultrasound were excluded. Gallbladder ultrasound and subject questionnaires were obtained in each trimester and at 4 to 6 weeks postpartum. Serum glucose, lipids, insulin, leptin, estradiol, and progesterone were measured at 26 to 28 weeks' gestation. A nested case-control study was done to examine the effects of serum leptin and insulin on incident gallbladder disease. At least two study ultrasounds were available for 3,254 women. Sludge or stones had been found on at least one study ultrasound in 5.1% by the second trimester, 7.9% by the third trimester, and 10.2% by 4 to 6 weeks postpartum. Regression of sludge and stones was common, such that overall 4.2% had new sludge or stones on the postpartum ultrasound. Twenty-eight women (0.8%) underwent cholecystectomy within the first year postpartum. Prepregnancy body mass index was a strong predictor of incident gallbladder disease (P < .001). Serum leptin was independently associated with gallbladder disease (odds ratio per 1 ng/dL increase, 1.05; 95% CI, 1.01, 1.11), even after adjusting for body mass index. In conclusion, incident gallbladder sludge and stones are common in pregnancy and the postpartum, and cholecystectomy is frequently done within the first year postpartum. Prepregnancy obesity and serum leptin are strong risk factors for pregnancy-associated gallbladder disease.