Abstract Deregulation of members of the transforming growth factor (TGF)-β signaling pathway occurs often in colon cancers and is believed to affect the formation of primary colon cancer. Mutational inactivation of TGFBR2 is the most common genetic event affecting the TGF-β signaling pathway and occurs in ∼20–30% of all colon cancers. By mating Fabpl4xat-132 Cre mice with Tgfbr2flx/flx mice, we have generated a mouse model that is null for Tgfbr2 in the colonic epithelium, and in this model system, we have assessed the effect of loss of TGF-β signaling in vivo on colon cancer formation induced by azoxymethane (AOM). We have observed a significant increase in the number of AOM-induced adenomas and adenocarcinomas in the Fabpl4xat-132 Cre Tgfbr2flx/flx mice compared with Tgfbr2flx/flx mice, which have intact TGF-β receptor type II (TGFBR2) in the colon epithelium, and we have found increased proliferation in the neoplasms occurring in the Fabpl4xat-132 Cre Tgfbr2flx/flx mice. These results implicate the loss of TGF-β-mediated growth inhibition as one of the in vivo mechanisms through which TGFBR2 inactivation contributes to colon cancer formation. Thus, we have demonstrated that loss of TGFBR2 in colon epithelial cells promotes the establishment and progression of AOM-induced colon neoplasms, providing evidence from an in vivo model system that TGFBR2 is a tumor suppressor gene in the colon.