Background: The addition of Bev to 5-Fluorouracil (5-FU)-based chemotherapy is the standard of care for previously untreated mCRC. A recent randomized trial demonstrated a 1.4 month increase in median overall survival (OS) when Bev is continued beyond the first progression, thus making it standard practice to use Bev with 5-FU based chemotherapy in both first- and second-line. International CEAs have evaluated Bev in the 1st-line setting. The objective of this study is to determine the cost effectiveness of Bev in the 1st line setting and when continued beyond progression from the US-payer perspective. Methods: We developed two Markov models to compare the cost and effectiveness of 5-FU, leucovorin and oxaliplatin (FOLFOX) with or without Bev in the first-line treatment, and subsequent chemotherapy with or without Bev in the second-line treatment of mCRC. Weibull models were fitted to the published survival curves, and were used to extrapolate the cause-specific mortality and progression risks. Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services, and drug costs based on the Medicare average sale prices (all in 2013 US $). Health outcomes were measured in life years (LY) and quality-adjusted life years (QALYS). The simulated OS and progression free survival (PFS) were validated by the fitted survival models. Model robustness was addressed by univariate and probabilistic sensitivity analyses (PSA). Results: Using Bev in first-line therapy provided an additional 0.289 QALYs (0.412 LYs) at a cost of $69,381. The incremental cost-effectiveness ratio (ICER) was $240,195/QALY. Continuing Bev beyond progression provided an additional 0.108 QALYs (0.167 LYs) at a cost of $23,788. The ICER was $219,742/QALY. In all one way sensitivity analyses, the ICER of Bev was > $100,000/QALY. The ICER of Bev was greater than $100,000/QALY in > 99.9% of PSAs. Conclusions: This is the first US based CEA of Bev in mCRC. Bev provides minimal incremental benefit at high incremental cost per QALY in both the first and second-line setting. The ICER of Bev could be improved by use of an effective biomarker to select patients most likely to benefit.