OBJECTIVES: To conduct a cost effectiveness analysis of anti-EGFR treatment regimes for the treatment refractory mCRC. Clinical trial data was available and utilized to examine panitumumab monotherapy and to compare cetuximab monotherapy vs cetuximab + irinotecan therapy, while indirect clinical trial data compared cetuximab based therapies with panitumumab monotherapy. METHODS: A Markov model comprising of three health states (stable disease, progressive disease and death), was developed from an US societal perspective to estimate economic implications of weekly anti-EGFR treatments for 52 weeks for 1000 treatment refractory mCRC patients. Transition probabilities were estimated based on available clinical literature data for each treatment. Therapy cost, health utilities, direct and indirect costs were based on published literature and national healthcare databases. Cost parameters were reported based on 2009 US dollars with a 3% discount rate. RESULTS: The analyses yielded an ICER of $249,035/QALY for cetuximab monotherapy vs cetuximab + irinotecan, an ICER of $266,196/QALY for cetuximab monotherapy vs. panitumumab, an ICER of $250,992/QALY for cetuximab + panitumumab and an ICER of $773,978/QALY for panitumumab vs. best supportive care (placebo). Through strictly increasing rankings of the ICERs, we find best supportive care to be most cost effective therapy, followed by panitumumab monotherapy, cetuximab monotherapy and cetuximab + irinotecan therapy; however, changes in model parameters may influence the rankings of the treatment regimes. CONCLUSIONS: Based on the willingness to pay threshold of $150,000/QALY, treating treatment refractory mCRC patient with anti-EGFR agents is not cost effective. However, since the clinical literature lacks comprehensive head to head clinical trial amongst all anti-EGFR agents, further research is necessary.