Purpose: Regorafenib is a standard-care option for treatment-refractory metastatic colorectal cancer that ncreases median overall survival by 6 weeks compared with placebo. Given this small incremental clinical benefit, we evaluated the cost-effectiveness of regorafenib in the third-line setting for patients with metastatic colorectal cancer from the US payer perspective Methods: We developed a Markov model to compare the cost and effectiveness of regorafenib with those of placebo in the third-line treatment of metastatic colorectal cancer. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2014. Model robustness was addressed in univariable and probabilistic sensitivity analyses Results: Regorafenib provided an additional 0.04 QALYs (0.13 life-years) at a cost of $40,000, resulting in an incremental cost-effectiveness ratio of $900,000 per QALY. The incremental costeffectiveness ratio for regorafenib was > $550,000 per QALY in all of our univariable and probabilistic sensitivity analyses. Conclusion: Regorafenib provides minimal incremental benefit at high incremental cost per QALY in the third-line management of metastatic colorectal cancer.