Background: Inflammatory bowel disease (IBD) results from the chronic dysregulation of the mucosal immune system and the aberrant activation of both the innate and the adaptive immune responses. We used two complementary models of colonic inflammation to examine the roles of interleukin (IL)‐19 in colonic inflammation and thus its possible role in IBD. Methods: Using gene‐targeting, we generated IL‐19‐deficient mice. To study the activation of the innate immune response during colonic inflammation we characterized an innate immune‐mediated model of colitis induced by dextran sulfate sodium (DSS). DSS can induce not only acute colitis but also chronic colitis. In addition to the acute DSS‐induced colitis model, we used a chronic DSS‐induced colitis model that is associated with the activation of both Th1 and Th2 cytokines as well as innate immune response in the colon. Results: We show that IL‐19‐deficient mice are more susceptible to experimental acute colitis induced by DSS, and this increased susceptibility is correlated with the accumulation of macrophages and the increased production of IFN‐γ, IL‐1β, IL‐6, IL‐12, TNF‐α, and KC. Additionally, cytokine production in IL‐19‐deficient macrophages was enhanced on stimulation of lipopolysaccharide (LPS) through reduced phosphorylation of STAT1 and STAT3. Moreover, our results clearly demonstrate that IL‐19 is required for B‐cell infiltration during chronic DSS‐induced colitis, which may be mediated by IL‐13 and IL‐6. Conclusions: The finding that IL‐19 drives pathogenic innate immune responses in the colon suggests that the selective targeting of IL‐19 may be an effective therapeutic approach in the treatment of human IBD. Inflamm Bowel Dis 2009