OBJECTIVE: To compare the cost-effectiveness of tandem mass spectrometry (MS/MS) screening for neonatal inherited metabolic diseases (IMDs) with fluorescence analysis (FA) screening for neonatal inherited metabolic diseases (IMDs) and provide evidence for promoting MS/MS in China. METHODS: An Excel-based decision tree model was constructed to evaluate the cost-effectiveness of MS/MS versus FA screening from a societal perspective. The model simulated the screening pathway, prevention, and treatment of IMDs, adjusted to 2023 price levels. Health outcomes were measured in quality-adjusted life years (QALYs), with a 3% annual discount rate applied. The willingness-to-pay (WTP) threshold was set at one times the per-capita GDP of China in 2023. RESULTS: MS/MS screening was more costly (CNY 1,121,637
USD 158,423 vs. CNY 380,276
USD 53,711) but more effective (16.47 QALYs vs. 5.93 QALYs) than FA screening. The incremental cost-effectiveness ratio (ICER) was CNY 70,286 (USD 9,927) per QALY, below the WTP threshold. The benefit-cost ratio (BCR) was 1:3.94. CONCLUSION: While MS/MS screening incurs higher costs, it achieves significantly greater QALY gains and demonstrates favorable cost-effectiveness and economic benefits. MS/MS screening should be actively promoted for neonatal IMDs in China.