BackgroundThe phase III RC48-C016 trial demonstrated that disitamab vedotin plus toripalimab (DV + T) provides significant survival benefits compared to chemotherapy in patients with HER2-expressing advanced urothelial cancer (UC), along with a favorable safety profile. However, its cost-effectiveness has not yet been evaluated. This study aims to evaluate the cost-effectiveness of DV + T versus chemotherapy as first-line treatment for HER2-expressing advanced UC from the perspective of the Chinese healthcare system.MethodsA partitioned survival model with a 15-year time horizon was developed to evaluate the cost-effectiveness of DV + T compared to chemotherapy. Outcomes included total cost, quality-adjusted life year (QALY), and the incremental cost-effectiveness ratio (ICER). Model uncertainty was examined through one-way and probabilistic sensitivity analyses.ResultsDV + T yielded 2.44 QALYs at a total cost of 98,514.95,whilechemotherapyyielded1.43QALYsatacostof98,514.95, while chemotherapy yielded 1.43 QALYs at a cost of 28,300.87. The ICER was 69,575.31perQALY.InChina,atawillingness−to−pay(WTP)thresholdof69,575.31 per QALY. In China, at a willingness-to-pay (WTP) threshold of 20,167.02 per QALY, DV + T has a 0% probability of being cost-effective as a first-line treatment for HER2-expressing advanced UC compared to chemotherapy. Subgroup analysis suggested that the ICER of DV + T versus chemotherapy tended to be substantially lower in patients ineligible to receive cisplatin (61,264.33perQALY)thaninthoseeligibleforcisplatin−basedchemotherapy(61,264.33 per QALY) than in those eligible for cisplatin-based chemotherapy (245,983.12 per QALY).ConclusionFrom the perspective of the Chinese healthcare system, DV + T is not cost-effective as first-line treatment for HER2-expressing advanced UC compared to chemotherapy.