Objective From the perspective of China's health system, to evaluate the cost-effectiveness of cetuximab β combined with FOLFIRI (irinotecan + calcium folinate + fluorouracil) compared to single-agent FOLFIRI as first-line treatment for RAS/BRAF wild-type metastatic colorectal cancer, providing economic evidence for clinical decision-making and medical insurance policy formulation. Method Based on a phase III clinical trial of cetuximab β combined with FOLFIRI, a three-state Markov model was constructed. The simulation cycle is 2 weeks (matching the FOLFIRI dosing regimen), and the simulation time range is 10 years (ensuring that 99% of cohort patients reach the death state). Output indicators include total cost and Quality-Adjusted Life Years (QALYs), to calculate the Incremental Cost Effectiveness Ratio (ICER); model robustness is verified through univariate sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis. Cost data is calculated based on the per capita GDP in 2024 at 95,700 yuan/person, with both cost and utility discount rates set at 5%. Results The basic analysis showed that the total cost of the cetuximab β + FOLFIRI group was 162,791 yuan, with a cumulative gain of 1.08 QALYs; the total cost of the FOLFIRI group alone was 47,846 yuan, with a cumulative gain of 0.91 QALYs. Compared to the FOLFIRI group alone, the incremental cost of the combination therapy group was 114,945 yuan, and the incremental QALYs were 0.17, with an ICER of 676,147 yuan/QALY, which is higher than three times the per capita GDP of China in 2024. Sensitivity analysis showed that scenario analysis and sensitivity analysis demonstrated the robustness of the model. In 99.9% of simulations, the incremental cost for each QALY gained by the cetuximab β combined with FOLFIRI group was above 287,100 yuan. Conclusion At a threshold of three times the per capita GDP in China, cetuximab β combined with FOLFIRI as first-line treatment for RAS/BRAF wild-type mCRC patients in China is not cost-effective compared to FOLFIRI alone.