OBJECTIVES: XELOX is the most utilised therapy for aCC in the UK. The aim of this analysis was to assess and compare the population net health benefit (pNHB) of all patients with aCC switching from the FOLFOX regimen to XELOX, from a UK National Health Service (NHS) perspective. METHODS: An indirect comparison of the NO16968 (XELOX) and MOSAIC (FOLFOX-4) trials was undertaken (where both regimens were compared to i.v. 5-FU plus FA) showing XELOX to be non-inferior. A cost minimisation approach was therefore taken. Drug costs were based on UK list prices taken from the British National Formulary (BNF 61), and additional costs such as administration costs, adverse event costs and pharmacy costs were taken from NHS reference costs, the literature and previous technology appraisals. A £20,000/QALY assumed displacement threshold was utilised to estimate the pNHB provided. Uncertainty was explored via one-way sensitivity analyses. RESULTS: Replacing FOLFOX-6 and FOLFOX-4 with XELOX saved £6490 and £9778 per patient respectively, of which £2434 and £1534 came from drug acquisition costs. Over 60% of the total savings were realised from reductions in the frequency of pharmacy use and administration resource use. The savings realised from full implementation of the XELOX regimen could be used by the NHS to generate more than 1000 QALYs over the next 5 years. The costs of AEs were similar across all three regimens. XELOX achieved savings of £3,400 per patient even when all parameters in the sensitivity analysis were simultaneously set to the worse case scenarios. CONCLUSIONS: XELOX has been demonstrated to be cost-effective and significantly cost-saving versus FOLFOX-4 and FOLFOX-6 in aCC from an NHS perspective. Full conversion of all aCC patients to XELOX could offer the NHS substantial financial savings and a significant pNHB of over 1000 QALYs over a 5 year period.