Introduction: The optimal Anti-VEGF (vascular endothelial growth factor) and Anti-EGFR (epithelial growth factor receptor) antibody regimen to combine with chemotherapy in the first-line treatment for metastatic colorectal cancer remains to be better defined. Results from randomized controlled trials are variable. Methods: A meta-analysis was performed by searching PubMed, Cochrane Registry, major oncology conferences proceedings until February 2010 for randomized controlled trials of Anti-VEGF and Anti-EGFR in first-line treatment of metastatic colorectal cancer. Summary estimates of progression-free survival, overall survival, overall response rate and 60- day mortality were derived. Effect of k-ras status was stratified in trials involving Anti-EGFR. Results: Nine trials were included, including three anti-VEGF +/- chemotherapy, n=2422; four anti-EGFR %plus;/- chemotherapy, n=4348 and two anti-VEGF with chemotherapy +/- anti-EGFR, n=1601. Adding anti-VEGF to chemotherapy showed a 20-30% risk reduction in disease progression and mortality, and a higher response rate. Benefit of anti-EGFR was seen only in k-ras wild type patients with 20% reduction in disease progression and 10% reduction of mortality. Adding both antibodies to chemotherapy showed worse survival outcomes. Conclusion: Benefit of adding anti-VEGF in first-line metastatic colorectal cancer treatment is well pronounced. Combining anti-EGFR with chemotherapy showed significant increase in response rate and PFS in k-ras wild type patients. Adding both antibodies to chemotherapy appeared inferior regardless of k-ras status.