ABSTRACT Background Treatment (tx) in RCTs might yield different outcomes than in clinical practice due to protocol-mandated intervention and follow up. We compared overall survival (OS) with 1st-line (1L) FOLFOX/XELOX + bevacizumab (BV) between mCRC pts in an RCT and pts in an OCS with matching eligibility. Methods Data sources were: 1) NO16966, an international RCT (2004 - 05 accrual; 2008 follow up) of FOLFOX/XELOX plus BV vs placebo for 1L mCRC; 2) ARIES, a US-based OCS of mCRC pts receiving 1L chemotherapy plus BV (2006–08 accrual; 2012 follow up). Analyses were restricted to pts who: 1) retrospectively met NO16966 eligibility criteria; 2) received FOLFOX/XELOX + BV; and 3) had no prior oxaliplatin. Cox proportional hazards models of OS were used to compare cohorts; adjusted analyses accounted for baseline (BL) and time-varying covariates including time on 1L tx, disease progression (PD), and use of BV beyond PD (BBP). Due to geographic differences in the cohorts, a sensitivity analysis compared all ARIES pts to NO16966 pts from US/Canada. Results Mean 1L tx duration was 242 days in ARIES (n = 755) vs 193 days in NO16966 (n = 624). Unadjusted analysis showed lower OS (ie, hazard ratio [HR] >1) for NO16966 pts. However, after adjusting for imbalances in BL differences, PD, and tx to and beyond PD, OS appeared comparable between cohorts (table). ECOG status of 0 (HR 0.79; 95% CI 0.69–0.89), history of primary tumor resection (HR 0.67; 95% CI 0.57–0.78), longer 1L tx duration (HR 0.95; 95% CI 0.94–0.97), and BBP (HR 0.77; 95% CI 0.65–0.91) were associated with longer OS, but >1 metastatic site (HR 1.29; 95% CI 1.13–1.47) and incidence of PD (HR 7.52; 95% CI 6.08–9.29) were associated with reduced OS. Sensitivity analyses of US/Canada pts showed similar results. Conclusions When comparing similar pts and adjusting for differences in tx patterns, OS appeared to be comparable with 1L FOLFOX/XELOX + BV in the NO16966 RCT vs the ARIES OCS. Analysis Hazard ratio for OS (95% confidence interval) Unadjusted analysis NO16966 patients (n = 624) vs ARIES patients (n = 755) 1.29 (1.14–1.46) Primary adjusted analysis* NO16966 patients (n = 624) vs ARIES patients (n = 755) 1.10 (0.95–1.29) Sensitivity adjusted analysis* NO16966 patients from US or Canada (n = 161) vs ARIES patients (n = 755) 0.94 (0.75–1.18) *Adjusted for age, gender, race, baseline ECOG performance status, history of cardiovascular disease, history of cardiovascular risk factors, initial diagnosis of cancer, 1L FOLFOX vs XELOX, number of metastatic sites, history of resection of primary tumor, months on 1L therapy, time-dependent PD at any time, and use of post-progression BV. Disclosure S.Y. Zafar: Dr Zafar has received honoraria from Roche/Genentech. A. Grothey: Dr Grothey is currently conducting research sponsored by Genentech, which is provided in the form of a grant to the Mayo Clinic. T. Bekaii-Saab: Dr Bekaii-Saab is a paid consultant to Bristol-Myers Squibb, Amgen, and Genentech, and has received honoraria from those companies. B. Sherrill: Beth Sherrill is an employee of a research organization that works under contract with multiple pharmaceutical companies. L. Bennett: Lee Bennett is an employee of a research organization that works under contract with multiple pharmaceutical companies. Y. Mun: Dr Mun is an employee of and holds stock options in Roche/Genentech. M. Sersch: Dr Sersch is an employee of, and holds stock options in Roche/Genentech. D. Dalal: Dr Dalal is an employee of and holds stock options in Roche/Genentech. H.I. Hurwitz: Dr Hurwitz has served in a consultant/advisory role for Genentech, Roche, Sanofi, Amgen, and BMS. He has received honoraria from Roche. Dr Hurwitz has received research funding from Roche, Genentech, Bristol-Myers Squibb, Sanofi, and Pfizer. All other authors have declared no conflicts of interest.