Germfree rats transgenic for the human genes HLA-B27 and beta 2-microglobulin were colonized with hemolysin-positive (Hly+) or hemolysin-negative (Hly-) strains of Listeria monocytogenes. HLA-B27 rats were very susceptible to infection with Hly+ L monocytogenes none survived beyond 6 days. Conversely, nontransgenic control rats survived alimentary tract colonization with the Hly+ strain, and both transgenic and nontransgenic rats survived colonization with the Hly- strain of L monocytogenes. After colonization with Hly+ L monocytogenes, both transgenic and nontransgenic rats developed severe bowel inflammation which consisted histologically of microab scesses, granulomatous lesions, and ulcers; however, whereas the transgenic rats died within 6 days, only very mild intestinal lesions were seen in nontransgenic rats 10 to 42 days after colonization. Liver and splenic lesions were small and transient in nontransgenic rats. Transgenic and nontransgenic control rats infected with Hly- Listeria developed mild transient diarrhea but showed no histological changes in the intestine. This study thus documents an association between a particular bacterial product (hemolysin produced by L monocytogenes) and the induction of severe inflammatory disease and death in rats expressing HLA-B27 and beta 2-microglobulin.