Objectives The aim of this study was to evaluate the cost-effectiveness of FOLFOXIRI/FOLFOXIRI compared with mFOLFOX6/FOLFIRI in first-line and second-line chemotherapy for metastatic colorectal cancer (mCRC) from the perspectives of the USA and China, respectively, and provide a decision-making basis for clinical selection of these two regimens.Design The study used a decision-analytic Markov model to simulate the process of mCRC, including three distinct health states: progression-free survival, progressive disease and death. Clinical data were derived from the TRIBE2 trial. Costs and utilities were obtained from local public databases and literature. One-way sensitivity analyses and probabilistic sensitivity analysis were also performed to explore the parameters' uncertainty in this study.Design The study used a decision-analytic Markov model to simulate the process of mCRC, including three distinct health states: progression-free survival, progressive disease and death. Clinical data were derived from the TRIBE2 trial. Costs and utilities were obtained from local public databases and literature. One-way sensitivity analyses and probabilistic sensitivity analysis were also performed to explore the parameters' uncertainty in this study.Participants The main included patients were histologically confirmed colorectal adenocarcinoma.Interventions First-line and second-line treatment with either FOLFOXIRI/FOLFOXIRI or mFOLFOX6/FOLFIRI.Main outcome measures Costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon as primary outcomes.Results Patients treated with the FOLFOXIRI/FOLFOXIRI regimen produced 0.08 QALYs in the USA while 0.04 QALYs in China compared with the mFOLFOX6/FOLFIRI regimen. The final ICERs for FOLFOXIRI/FOLFOXIRI were US$5127.70 per QALY and US$30 478.33 per QALY in the USA and China, which are below the willingness-to-pay (WTP) thresholds. In the USA, when the WTP was US$100 000 for each QALY gained, the probability was nearly 99.6% that the FOLFOXIRI/FOLFOXIRI treatment was cost-effective. In China, when the WTP was US$36 053.01 (3 x GDP) for each QALY gained, the probability was nearly 54.7% that FOLFOXIRI/FOLFOXIRI treatment was cost-effective.Conclusion Patients with mCRC treated with FOLFOXIRI/FOLFOXIRI as first-line and second-line chemotherapy may improve health outcomes and expend financial resources more efficiently than mFOLFOX6/FOLFIRI whether in China or the USA, which benefits not only individual survival but also the health care system from a value perspective.