A high prevalence (71%) of gallstones was noted in free-ranging cottonrats, Sigmodon hispidus, collected from one site in Lubbock County, Texas. The gallbladder of affected animals was distended and filled with white, soft, friable, cholesterol gallstones of variable sizes. Focal hyperplasia of the epithelium and connective tissue layer of the gallbladder was evident in affected cottonrats. As the forage available to affected animals was different from that available to gallstone-free animals collected from other areas, this may be the cause of the higher prevalence of cholelithiasis in this population. The significance of this disease and possible use of the cottonrat as an experimental model are discussed.