We have studied the relationship between gallstones and gallbladder cancer in American Indians located in the southwestern United States. As determined in a case-control study, the overall age- and sex-adjusted relative risk for this group was 20.9 (95 percent confidence interval 8.1-54). The corresponding relative risk for non-Indian subjects was significantly less: 4.4 (95 percent confidence interval 2.6-7.3). Indian subjects were more likely to have stones >cm than non-Indian subjects: Age-adjusted odds ratio = 1.5, 95 percent confidence interval 1.2-2.00. Large stones appear to be associated with an increased risk of gallbladder cancer, perhaps because they have been present longer than small stones. Many other Native American populations in the Western Hemisphere ranging from Alaska to South America are also prone to gallbladder cancer. These widely separated groups may share a common genetic factor leading first to obesity and then to gallstones and gallbladder cancer.