Background & Aims Epidemiology studies have shown that obesity increases risk for colorectal cancer (CRC). We investigated the contribution of obesity-induced increases in levels of tumor necrosis factor (TNF)-α and hyperinsulinemia to the development of CRC in mice. Methods Lean and obese mice (C57BL6/J and ob/ob ) were given a combination of azoxymethane and dextran sulfate sodium, which led to the development of CRC; lean and obese severe combined immunodeficient mice were injected with HT-29 cells. We analyzed the roles of TNF-α and insulin in the development of obesity-mediated CRC using immunoblot, immunohistochemical, and apoptosis assays. Results Genetic- and diet-induced obesity increased the incidence and size of tumors that developed after administration of azoxymethane and dextran sulfate sodium, compared with lean mice. HT-29 xenograft tumors grew more rapidly in obese than lean mice. Neutralization of TNF-α reduced activation of c-Jun N-terminal kinase, IκB kinase, and the phosphatidylinositol 3-kinase–Akt–mammalian target of rapamycin signaling pathway; it also reduced the growth and development of tumors in obese mice. Reducing levels of insulin levels had no effect on tumor growth in obese mice. Conclusions TNF-α contributes to colon tumor growth in obese mice. Reagents that inhibit TNF-α might prevent the development or progression of CRC in obese individuals.