Enterohepatic Helicobacter species (EHS) often are associated with typhlocolitis and rectal prolapse in mice. We sought to describe rectal prolapses histologically, relate lesions to mouse genotype and EHS infection status, and characterize EHS pathogens on our campus. Our mouse population was housed among 6 facilities on our main campus and a seventh, nearby facility. We investigated cases of rectal prolapse over 1 y and included 76 mice, which were broadly categorized according to genotype. Microscopically, lesions ranged from mild to severe typhlocolitis, often with hyperplastic and dysplastic foci. Neoplastic foci tended to occur at the ileocecal-colic junction. Lesions were most severe in strains that had lower-bowel inflammatory disease, notably IL10, Rag1, and Rag2 knockout strains; prolapses occurred in these strains when housed both in areas with endemic EHS and in our Helicobacter-free barrier facility. Most mice with rectal prolapses were immunocompromised genetically modified mice; however, the most frequently sampled strain, the lamellipodin knockout, was noteworthy for its high incidence of rectal prolapse, localized distal colonic and rectal lesions, and lack of known immunodeficiency. This strain is being explored as a model of rectal carcinoma. Most of the colons examined tested PCR-positive for EHS, often with coinfections. Although H. bilis is prevalent on our campus, we did not find this organism in any mice exhibiting clinical signs of rectal prolapse. Identification of H. apodemus in 22% of cases has fueled increased surveillance on our campus to characterize this organism and differentiate it from the closely related H. rodentium.