Although obesity is a well-recognized risk factor for gallstones, the excess risks associated with higher levels of obesity and recent weight change are poorly quantified. We evaluated these issues in the Nurses' Health Study. Among 90,302 women aged 34-59 y at baseline followed from 1980 to 1988, 2122 cases of newly diagnosed symptomatic gallstones occurred during 607,104 person-years of follow-up. From 1980 to 1986, 488 cases of newly diagnosed unremoved gallstones were documented. We observed a striking monotonic increase in gallstone disease risk with obesity; women with a body mass index (BMI) greater than 45 kg/m2 had a sevenfold excess risk compared with those whose BMI was less than 24 kg/m2. Women with a BMI greater than 30 kg/m2 had a yearly gallstone incidence of greater than 1% and those with a BMI greater than or equal to 45 kg/m2 had a rate of approximately 2%/y. Recent weight loss was associated with a modestly increased risk after adjustment for BMI before weight loss. Current smoking was an independent risk factor; women smoking greater than or equal to 35 cigarettes/d had a relative risk of 1.5 (95% CI 1.2-1.9).