Large bowel disease detected clinically by rectal prolapse was studied in 64 immunodeficient mice (37 athymic NCr-nu/nu, 12 BALB/c AnNCr-nu/nu, 9 C57BL/6NCr-nu/nu, and 6 C.B17/Icr-scid/NCr) naturally infected with Helicobacter hepaticus. Rectal prolapse was found in approximately 5% of immunodeficient mice maintained in a research facility over a period of 3.5 years. All mice had various degrees of chronic proliferative typhlitis, colitis, and proctitis, usually without concomitant hepatitis. Some mice had severe proliferative proctitis with cystic hyperplasia. Histologic study of the large bowel of 48 athymic NCr-nu/nu mice without H. hepaticus infection and housed in another clean facility revealed only 12% of the mice with minimal-to-mild large bowel inflammation. Helicobacter hepaticus infection is associated with large bowel disease in immunodeficient mice but is not seen in H. hepaticus-infected immunocompetent mice. This new pathogenic bacterial infection should be considered as another potential cause or co-factor for rectal prolapse and large bowel disease in mice.