Gallstones are a major risk factor for gallbladder cancer, but few persons with stones experience development of tumors. To examine this relationship, a case-control study was performed. Each of 81 cancer cases was matched for age, sex, hospital and admission date with 2 controls, one with benign gallbladder disease and one with a nongallbladder diagnosis. Persons with large gallstones were found to be at increased risk for cancer. For those with stone diameters of 2.0-2.9 cm, the odds ratio (v stone size < 1 cm) was 2.4; for stones 3 cm or larger, the ratio was 10.1. This association of large gallstones with cancer was not hypothesized before data analysis and should be replicated in other settings before being accepted. If confirmed, this finding might have implications for the management of silent gallstones.