The relationship between gallstones and gallbladder cancer was investigated in a case-control study in 131 subjects with gallbladder cancer and 2,399 subjects without gallbladder cancer. Included in the study were male and female subjects from 3 racial groups: white, black, and Southwestern American Indian. For the non-Indian group there was a significant relationship between gallstones and gallbladder cancer, with an overall estimated relative risk (RR) of 4.4 (95% confidence interval, 2.6-7.3). For the Indian population the overall estimated RR was much higher: RR = 20.9; 95% confidence interval = 8.1-54. By the combination of the RR, the prevalence of gallstones, and the overall incidence of gallbladder cancer, the risk of gallbladder cancer was calculated in each population for subjects with untreated gallstones. In older subjects with gallstones the estimated 20-year cumulative risk for gallbladder cancer ranged from 0.13% in black males to 1.5% in Indian females. It was concluded that the risk of gallbladder cancer in untreated subjects with gallstones is heterogeneous, depending on race and sex as well as the period of exposure to gallstones.