© 2015 Elsevier Inc. Background Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy in combination with chemotherapy in the first-line therapy of advanced colorectal cancer (CRC). Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting, and their comparative efficacy remains unclear. We aimed to evaluate the impact of these targeted therapies on patient outcomes by combining the data from randomized clinical trials. Materials and Methods MEDLINE, PubMed, EMBASE, and meeting proceedings within the past 12 months were searched to identify relevant studies. All randomized phase II/III clinical trials of advanced CRC comparing an anti-EGFR therapy with an anti-VEGF agent in the first-line setting were included. Data were extracted on sample size, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results Three randomized studies comprising 2014 participants were included in the meta-analysis. For patients with KRAS wild type (KRAS-WT) CRC, the ORR was superior in patients who received first-line anti-EGFR therapy compared with those who received anti-VEGF therapy (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.09-1.58; P =.004). This effect was even stronger for all RAS-WT patients (OR, 1.46; 95% CI, 1.13-1.90; P =.004). There was no difference in PFS overall irrespective of the KRAS-WT (HR, 1.03; 95% CI, 0.93-1.13; P =.61) or all RAS-WT (HR, 0.92; 95% CI, 0.71-1.18; P =.50) status. The OS was significantly longer in the patients who received first-line anti-EGFR therapy compared with those who received anti-VEGF therapy (KRAS-WT: HR, 0.79; 95% CI, 0.65-0.97; P =.026; all RAS-WT: HR, 0.77; 95% CI, 0.63-0.95; P =.016). Conclusion The results of our research show superior ORR and OS with first-line anti-EGFR therapy compared with anti-VEGF therapy in both KRAS-WT and all RAS-WT patients with advanced CRC. These results suggest that anti-EGFR monoclonal antibodies may be a real alternative to anti-VEGF therapy as initial treatment of advanced CRC.