OBJECTIVES: Liver resection is a treatment offering long-term survival in patients with metastatic colorectal cancer (mCRC). However, the majority of such patients are not suitable for curative hepatectomy due to widespread nature of their disease. Chemotherapy can significantly downsize primarily unresectable metastases and increase the possibility of resection in mCRC patients. It has been shown that chemotherapy combined with biological agents, cetuximab (CET) and panitumumab (PAN), is clinically beneficial for treating RAS WT tumors (tumors without mutations in KRAS/NRAS exons 2/3/4). This study is aimed: (1) to estimate the cost-effectiveness of combination chemotherapies with CET and PAN for people with previously untreated RAS WT mCRC, not eligible for liver surgery; and (2) to assess CET and PAN against the National Institute for Health and Care Excellence (NICE) end-of-life (EoL) criteria, to inform a Health Technology Assessment for NICE. METHODS: We proposed an economic model estimating costs and benefits of mCRC treatments over patient lifetime horizon. In our base case, we calculated incremental cost-effectiveness ratio (ICER) for CET+FOLFOX versus FOLFOX, PAN+FOLFOX versus FOLFOX, and CET+FOLFIRI versus FOLFIRI. Probabilistic and univariate deterministic sensitivity analyses were performed to evaluate uncertainty in model predictions. The cost-utility analysis was based on five randomised controlled trials and undertaken from the NHS and personal social service perspective. Estimated costs and quality-adjusted life years were discounted at 3.5% per annum. RESULTS: CET and PAN are not cost-effective at willingness-to-pay thresholds of £20,000. Moreover, ICERs remain above £20,000 even under zero prices for CET and PAN. Based on the available evidence, neither CET nor PAN fulfils the NICE EoL criteria to be considered as life-extending EoL treatments. CONCLUSIONS: Although CET and PAN appear to be clinically beneficial for RAS WT patients, they are likely to represent poor value for money when judged by cost-effectiveness criteria used in England and Wales.