OBJECTIVES: To estimate the cost-effectiveness of cetuximab plus best supportive care (BSC) or cetuximab plus chemotherapy in patients with EGFR-expressing KRAS wild-type metastatic colorectal cancer who have failed at least two previous chemotherapeutic regimens in the metastatic setting from the UK NHS perspective. METHODS: A Markov model was developed to inform the cost-effectiveness (CE) of cetuximab plus BSC and cetuximab plus chemotherapy both versus BSC, and additionally the CE of cetuximab plus BSC and cetuximab plus chemotherapy both versus panitumumab plus BSC. Progression-free survival and overall survival data were collected from the following clinical trials: Karapetis et al. 2008, De Roock et al. 2007 and 2010, and Amado et al. 2008. These three clinical studies were relevant to perform indirect treatment comparisons. RESULTS: In the base-case analysis, treatments with cetuximab resulted in additional QALY as follows: cetuximab plus BSC versus BSC (0.303), cetuximab plus chemotherapy versus BSC (0.668), cetuximab plus BSC versus panitumumab plus BSC (0.193), and cetuximab plus chemotherapy versus panitumumab plus BSC (0.616). The base-case incremental cost effectiveness ratios (ICER) for cetuximab plus BSC and cetuximab plus chemotherapy, both compared to BSC are in the region of £50,000 per QALY. Compared to panitumumab plus BSC, the ICERs are below the NICE’s £30,000 willingness-to-pay threshold. CONCLUSIONS: Weighting the QALYs gained with the NICE supplementary advice, suggests that cetuximab plus BSC or cetuximab plus chemotherapy is potentially a cost-effective use of NHS resources in this setting.