Background: Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. It is the third most common cancer worldwide and the fourth most common cause of cancer-related death. FOLFOX, a combination of leucovorin calcium, fluorouracil, and oxaliplatin, is the first-line chemotherapy for stage III and stage IV CRC. However, patients with FOLFOX-resistant CRC have a poor prognosis. In recent years, virochemotherapy has been proposed as a potential treatment for chemotherapy-resistant cancer. Materials and Methods: Through our first screening assay, we found that coxsackievirus A11 (CVA11) displayed potent oncolytic activities. We tested whether coxsackievirus A11 (CVA11) has oncolytic activity in human CRC cells in vitro and in vivo. We also examined whether pretreatment of oxaliplatin-resistant CRC cells with oxaliplatin enhances the oncolytic activity of CVA11. Results: We found that CVA11 was potently oncolytic against the oxaliplatin-sensitive Caco-2 cell line, but had little effect on the oxaliplatin-resistant line WiDr. However, pretreatment of WiDr cells with oxaliplatin enhanced the oncolytic activity of CVA11, and the combination therapy was more cytotoxic than either oxaliplatin treatment or CVA11 infection alone. Furthermore, growth of subcutaneous WiDr tumors in a xenograft model was significantly lower in mice treated with oxaliplatin followed by intratumoral CVA11 injection compared with mice receiving either treatment alone. Conclusion: Oxaliplatin pretreatment sensitized oxaliplatin-resistant CRC cells to lysis by CVA11 infection in vitro and in vivo. Taken together, these findings identify a novel potential chemovirotherapeutic modality for the treatment of oxaliplatin-resistant human CRC.