In a colony of cotton rats (Sigmodon hispidus) consisting of 258 female and 283 male animals, 61 females and 2 males had a gastric mucosal lesion. This lesion developed in rats over 2 months of age, with a gradual increase in incidence thereafter. The lesion was grossly characterized by diffuse, often irregular thickening of the fundic mucosa, but the antrum was not affected. In 46% of the rats with this lesion, the serosal surface of the stomach was also involved. There was no evidence of disseminating or blood-borne metastasis. Histologically the mucosal thickening indicated a monotonous, diffuse proliferation of gastric glands with slight nuclear atypia, interpreted to be adenomatous hyperplasia. Invasion into submucosal, muscular, and subserosal layers by neoplastic cells with more atypia than the adenomatous hyperplasia was also noted and interpreted to be a tubular adenocarcinoma. In the adenocarcinoma lesions the infiltrating glands were surrounded by a desmoplastic reaction. In several of the adenocarcinoma lesions there were poorly differentiated adenocarcinoma cells with distorted gland formation. Lesions were diagnosed by soft X-ray examination with barium, without the need for laparotomy. Because these combined data demonstrate the spontaneous occurrence of gastric adenocarcinoma in the background of adenomatous hyperplasia, this cotton rat model can be used to examine, in minute detail, multistep carcinogenesis in the digestive tract.