Lawsonia intracellularis is a recently identified bacterial pathogen which causes disease in a broad range of animals. Invasion of intestinal epithelial cells and the resultant hyperplasia of infected cells are central processes in disease pathogenesis. In this study, we aimed to establish whether immunocompetent mice were susceptible to infection and whether gamma interferon (IFN-γ) contributed to the pathogenesis of infection. Wild-type 129-Sv-Ev mice (129 mice) and IFN-γ receptor knockout mice based on the 129 background (IFN-γR−) were challenged orally with approximately 5.5 × 107 L. intracellularis cells. Both 129 and IFN-γR− mice became infected, although the extent of infection (as determined by the proportion of infected crypts) was substantially lower in 129 mice than in IFN-γR− mice. Despite these differences, infected crypts showed characteristics typical of proliferative enteropathies of other animals, i.e., intracellular colonization of epithelial cells by L. intracellularis with resultant epithelial hyperplasia. Infection in 129 mice was cleared between days 21 and 28 postchallenge, whereas infection in IFN-γR− mice was evident in 100% of animals from day 21 onward. Additionally, in IFN-γR− mice the infection was so extensive that fatalities resulted. IFN-γ therefore plays a significant role in limiting intracellular infection and increased cellular proliferation associated with L. intracellularis. L. intracellularis infection is generally associated with modest cellular infiltration; therefore, further comparative examinations will be necessary to determine pathogenicity factors and define the role of IFN-γ in controlling this infection.