There is currently a lack of therapeutic options for patients with advanced colon cancer. Although certain chemotherapies are able to suppress the progression slightly, the response rate is low, and side effects of treatment and tumor recurrence continue to present problems for clinicians. Tumor necrosis factor-α (TNF-α) has been identified to possess tumor-promoting properties. In the present study, the effect of anti-TNF-α treatment (infliximab) in combination with chemotherapy on colon cancer was investigated. Tumor tissue samples were collected from patients with colon cancer who received oxaliplatin (OXA) treatment. Their TNF-α expression levels were examined with regard to their sensitivity to OXA. OXA-resistant colon cancer cell lines were established to explore the effects of anti-TNF-α treatment and OXA treatment. Furthermore, an OXA-resistant colon cancer xenograft mouse model was created and the effects of the combination treatment of anti-TNF-α and OXA on the mice were assessed. The results of the present study indicated that TNF-α was increased in the tumor tissue of patients with colon cancer who were resistant to OXA and also in OXA-resistant colon cancer cell lines. Anti-TNF-α treatment using infliximab inhibited the survival of OXA-resistant colon cancer cell lines by inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effects. The combination of infliximab and OXA treatment achieved increased efficacy on the OXA-resistant colon cancer xenograft mouse model compared with treatment with OXA alone. On the basis of the results of the present study, it was concluded that infliximab may sensitize colon cancer cells to OXA treatment.