CD4⁺CD25⁺Foxp3⁺ Regulatory T cells (Treg) have been implicated in the maintenance of immune homeostasis in large intestine, the most common site for inflammatory bowel disease (IBD).  To determine the role of Treg cells during colonic inflammation, we examined the course and outcome of Citrobacter rodentium infection in mice depleted of Treg cells. Interestingly, we found that mice depleted of Treg cells are more susceptible to mucosal C. rodentium infection than non-depleted mice. Treg-depleted mice exhibited exacerbated weight loss, significantly higher bacterial burden in the colon, increased dissemination to systemic tissue and colonic pathology.  Compared to non-depleted mice, at 5 days after infection depleted mice showed altered expression of inflammatory cytokines and antimicrobial peptides in the colon, which have been shown to be protective against C. rodentium infection. These data indicate that Treg cells are important in maintaining the host immune response in the colon and provide new therapeutic insights for IBD.