Pathogenesis studies of M. paratuberculosis infection in ruminants are hampered by the long incubation time of the disease. Although small rodents are usually considered to be resistant to M. paratuberculosis infection, several murine strains with higher susceptibility have been found. There are no detailed reports with regard to susceptibility in rats. The Lewis rat is a valuable model for inflammatory bowel disease studies as well as immune mediated disorders involving mycobacteria as inducing agents. Thus we decided to use the Lewis rat to investigate its potential as a small laboratory animal model for paratuberculosis. In total 24 female Lewis rats were orally inoculated with M. paratuberculosis. The rats were first inoculated at 3 weeks of age, and 12 more inoculations followed in a decreasing frequency during the 3 months to follow. Twelve control rats received a sham inoculation. At regular intervals rats from each group were sacrificed and immunological and histopathological examinations were performed on the gastrointestinal tract, the liver and the spleen over a nine month period. None of the rats developed lesions which were indicative of mycobacterial infection as determined by histology with HE and Ziehl-Neelsen staining. The bacteria could not be recultured from samples taken from the gut, the liver or the spleen. Some of the immunological tests however, showed evidence that bacteria had entered via the intestinal tract. We conclude that Lewis rats are resistant to oral challenge with M. paratuberculosis, and can not serve as a model in studying the immunopathogenesis of paratuberculosis.