Epidemiologic studies associate low serum vitamin D levels with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD). 129-Smad3tm1Par/J (Smad3-/-) mice are a model of bacterial-driven colitis and colon cancer when infected with Helicobacter bilis. Thus, we used this mouse model to determine whether increased dietary vitamin D would reduce inflammation and colon cancer. Smad3-/- mice were fed purified diet with either maintenance (1 IU vitamin D/g diet; maintenance) or increased concentrations of vitamin D (5 IU vitamin D/g diet; high vitamin D). One week after diet initiation, mice were inoculated with broth or H. bilis and were necropsied at several time points post-inoculation to assess inflammation, dysplasia, and neoplasia incidence. At 16 weeks post infection, 11% of mice fed high vitamin D diet had cancer compared to 41% of mice fed maintenance diet (p=0.0121). Evaluation at an early time point (1 week post-infection) showed that animals fed high vitamin D had decreased MAPK (p-p38 and p-JNK) activation in lamina propria leukocytes as well as decreased NFκB activation in colonic epithelial cells. Reduction in MAPK and NFκB activation correlated with decreased IBD scores (2.7 vs 15.5, p<0.0001) as well as decreased inflammatory cell infiltrates and reduced expression of proinflammatory cytokines in cecal tissue. These findings suggest that increased dietary vitamin D is beneficial in preventing inflammation-associated colon cancer through suppression of inflammatory responses during initiation of neoplasia or early stage carcinogenesis.