Background: The likelihood of converting unresectable metastatic colorectal cancer (CRC) to operable disease with systemic therapy is unknown. The purpose of this study was to determine the proportion of patients with unresectable CRC metastases that become resectable on combination systemic therapy, and whether biologic agents (antiantiogenics, anti-EGFR and multitargeted agents) improve the rate of resection (primary outcome). Methods: We searched Medline, Embase, CENTRAL and PubMed for randomized controlled trials comparing chemotherapy and biologics (intervention) vs. combination chemotherapy alone (control) in patients with unresectable CRC metastases. Study selection, data abstraction, risk of bias and quality of the evidence assessment were carried out in duplicate. Secondary outcomes included overall survival (OS) and progression free survival (PFS). Risk of bias was assessed using the Cochrane tool. Statistical heterogeneity was calculated using chi-squared and I2. Clinical heterogeneity was explored via subgroup analyses. The quality of the evidence was assessed using GRADE. Protocol was published in PROSPERO. Results: Of 7954 abstracts retrieved, 12 studies were analyzed and 8 reported the primary outcome, with 2604 intervention and 2661 control patients. The proportion of patients resected was higher in the intervention group, Relative Risk 1.36, 95% confidence interval (CI) 1.08-1.69, p = 0.008. The absolute risk of undergoing resection was 48 per 1000 (control); compared to 65 per 1000 (intervention). There was no difference in OS, Hazard Ratio (HR) 0.91, 95% CI 0.82-1.01. PFS was better in the intervention group (HR 0.83, 95% CI 0.74-0.92). Overall the risk of bias for the included studies was low. Statistical test for heterogeneity was low (I2 was 0%, p = 0.72). There was significant clinical heterogeneity, which was not explained with subgroup analyses. The quality of the evidence (GRADE) was moderate. Conclusions: The addition of biologic agents to systemic chemotherapy in patients with unresectable CRC metastasis improves resectability and PFS but not OS.