Background Up to 60% to 80% of colorectal cancer (CRCs) exhibit epithelial growth factor receptors (EGFR). EGFR promotes cancer in a number of ways, some of which include cell cycle disruption and others that involve signaling through a variety of downstream pathways. Objective The aim of the current study is to evaluate the role of Anti-Epithelial Growth Factor Receptors (Anti-EGFR) in management of metastatic colorectal cancer. Patients and methods A comparative study was conducted in Medical Oncology Departments in Zagazig University and Maadi Military Hospital including all metastatic colorectal cancer patients from January 2016 to January 2018, with total of 186 patients. All patients were evaluated regarding epidemiological data and response to treatment and survival analysis. Results Median overall survival of whole studied samples (N=186 patients) was 22 months and was higher in patients receiving Anti-EGFR. Among the studied group, patients with wild Kirsten rat sarcoma virus (KRAS) were 73 patients out of which 47 (64.3%) patients received anti–EGFR and chemotherapy and 26 (35.6%) received chemotherapy alone, with overall survival 32 vs. 27 months (P=0.217) and progression free survival 9 vs. 8 months (P=0.824), respectively. Overall survival had significant correlations with receiving previous adjuvant treatment (P=0.001), resection of primary tumor (P=0.001), and site of metastasis with lymph nodes metastasis showing best overall survival up to 39 months (P=0.02). Conclusion Anti-EGFR was beneficial in improving progression-free survival and response rates and overall survival for patients with metastatic …