Background and Aims: SAMP1/Yit mice spontaneously develop chronic terminal ileitis, reminiscent of the human disease described by Crohn et al. in 1932. Several new phenotypic features have appeared in our colony after more than 20 generations of brother-sister mating. In this report, we describe the distinguishing features of the SAMP1/YitFc substrain at the University of Virginia, compared with the Japanese SAMP1/Yit parental strain. Methods: A colony of SAMP1/Yit mice was established at the University of Virginia in 1996, from 2 breeding pairs obtained from Japan. A systematic characterization of their phenotypic and immunologic characteristics was performed at 4, 10, 40, and more than 60 weeks of age. Results: The following differences were observed: (1) SAMP1/YitFc mice displayed established ileitis as early as 10 weeks of age, (2) the incidence of skin lesions inversely correlated with the occurrence of intestinal inflammation, (3) mice develop chronic ileitis with prominent muscular hypertrophy and focal collagen deposition in inflamed segments, (4) mesenteric lymph node lymphocytes acquired an activated phenotype coincident with disease progression, (5) high interferon-γ production was detected by 4 weeks of age and preceded the onset of ileitis, and (6) a subgroup of mice (∼5%) developed perianal disease with ulceration and fistulae. Conclusions: The SAMP1/YitFc substrain exhibits unique characteristics when compared with the original Japanese strain. Of particular interest is the emergence of perianal fistulizing disease, to our knowledge the first report of such occurrence in an animal model of inflammatory bowel disease.