Risk factors for the development of gallstones during rapid weight loss were assessed in 457 subjects who entered a weight control program (520 kcal/day). Absence of gallstones in these subjects was documented by ultrasonography prior to entry into the study. Ultrasonography was performed again at 16 weeks on the subjects who remained in the study (N = 248). The incidence of gallstones by 16 weeks of rapid weight loss was 10.9% (27/248). Most factors associated with gallstones in the general population, eg, older age, female gender, parity, positive family history, etc, were not associated with gallstones in this population. The risk factors for developing gallstones included increased initial body mass index [weight (kg)/height (m)2], amount of body mass index loss, and serum triglyceride levels. The positive predictive value of these risk factors was 75%, but the sensitivity was only 12%. These observations indicate that risk factors for the development of gallstones during rapid weight loss are probably different from those in the general population. The factors identified by this study are useful in predicting patients at high risk for gallstones. However, since only a minority of gallstones that form can be predicted, further study is needed to identify additional factors that will improve our ability to predict gallstone formation.