Background/Aims: C3H/HeJ mice at the Jackson Laboratory have periodically been culled because of the occurrence of soft feces, perianal ulceration, and rightsided colitis. No pathogens have been isolated. The goal of the current study was to establish a substrain with a high incidence of this disease. Methods: Affected male and female C3H/HeJ mice were bred. The clinical, pathological, microbiological, and genetic features of 216 mice of the resulting pedigree were characterized. Results: A severely affected female crossed with a normal male resulted in a new substrain, denoted C3H/HeJBir, with a high incidence of right-sided colitis. Histologically, lesions occurred primarily in the cecum and proximal colon, characterized by acute and chronic inflammation, crypt abscesses, ulcerations, regenerative hyperplasia, and submucosal scarring. Such colitis peaked at 3-6 weeks; however, similar disease was found sporadically in animals more than 1 year of age. Small lesions at the anorectal junction were common throughout life. An extensive search for pathogens was negative. Genetic analysis of C3H/HeJBir mice suggested that the disease was inherited as a quantitative trait. Conclusions: C3H/HeJBir mice develop a spontaneous, heritable form of idiopathic inflammatory bowel disease and will be a valuable resource for genetic and immunologic studies of this disease. © 1994.