Persistent murine infection with Helicobacter hepaticus leads to chronic gastrointestinal inflammation and neoplasia in susceptible strains. To determine the role of the virulence factor cytolethal distending toxin (CDT) in the pathogenesis of this organism, interleukin-10-deficient (IL-10^−/−) mice were experimentally infected with wild-type H. hepaticus and a CDT-deficient isogenic mutant. Both wild-type H. hepaticus and the CDT-deficient mutant successfully colonized IL-10^−/− mice, and they reached similar tissue levels by 6 weeks after infection. Only animals infected with wild-type type H. hepaticus developed significant typhlocolitis. However, by 4 months after infection, the CDT-deficient mutant was no longer detectable in IL-10^−/− mice, whereas wild-type H. hepaticus persisted for the 8-month duration of the experiment. Animals infected with wild-type H. hepaticus exhibited severe typhlocolitis at 8 months after infection, while animals originally challenged with the CDT-deficient mutant had minimal cecal inflammation at this time point. In follow-up experiments, animals that cleared infection with the CDT-deficient mutant were protected from rechallenge with either mutant or wild-type H. hepaticus. Animals infected with wild-type H. hepaticus developed serum immunoglobulin G1 (IgG1) and IgG2c responses against H. hepaticus, while animals challenged with the CDT-deficient mutant developed significantly lower IgG2c responses and failed to mount IgG1 responses against H. hepaticus. These results suggest that CDT plays a key immunomodulatory role that allows persistence of H. hepaticus and that in IL-10^−/− mice this alteration of the host immune response results in the development of colitis.