OBJECTIVES: The cost-effectiveness of cetuximab has been controversial mainly because of its marginal clinical benefits at very high medication cost. This study examines the cost-effectiveness of cetuximab versus best supportive care in the patients with metastatic colorectal cancer in US from the perspective of Medicare. METHODS: As modeled in a decision tree, three treatment options (cetuximab, cetuximab plus irinotecan, and best supportive care) are evaluated clinically and economically. Costs of cetuximab treatment options are largely determined by the treatment responses: complete or partial responsive, stable disease, or progressive, and whether or not the patient experienced severe infusion reaction and/or severe adverse events. The primary outcome is quality-adjusted life expectancy. The treatment response rates and quality of life measurements are based on the results from clinical trials. Incremental cost-effectiveness ratios (ICER) between cetuximab treatments and best supportive care are presented to demonstrate the value of cetuximab treatments. Finally, sensitivity analyses are conduct to test the robustness of the results. RESULTS: In the patients with metastatic colorectal caner, the incremental cost per quality-adjusted life year (QALY) was $336,218 for cetuximab, and $318,609 for cetuximab plus irinotecan, in comparison with best supportive care. One-way sensitivity analyses showed that the cost of cetuximab had the highest impact on ICERs, compared to other costs and quality of life parameters. Probabilistic sensitivity analyses by Monte Carlo simulation demonstrated that best supportive care is more cost-effective than cetuximab treatments until the threshold of willingness to pay is raised up to $240,000. CONCLUSIONS: Our analyses suggest that cetuximab is not cost-effective, either in monotherapy or in combination with irinotecan, as the cost-effectiveness ratios are far beyond the accepted threshold of $50,000 per QALY gained. Cetuximab treatments need to be carefully evaluated before being delivered to metastatic colorectal cancer patients.