The efficacy of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) has been proved in the treatment of left-sided RAS wild-type unresectable metastatic colorectal cancer. However, their effectiveness in the early stages of the disease has been questioned. Previous studies have shown that the use of these drugs in an adjuvant setting was not effective and recent evidence suggests that they are also ineffective in patients with resectable liver metastases. Neoadjuvant therapy is currently the standard of care for many types of cancer, and studies in this field are ongoing. There is limited data available on the efficacy of anti-EGFR MoAbs in the treatment of locally advanced colon cancer, and a recent study showed no benefit. This review focused on the perioperative use of anti-EGFR MoAbs in the treatment of resectable colon cancer and explored possible explanations for their low effectiveness.