BACKGROUND: To evaluate the cost-effectiveness of Enfortumab vedotin and pembrolizumab (EVP) as a new first-line treatment option for advanced urothelial carcinoma compared to standard chemotherapy (gemcitabine with cisplatin or carboplatin) from the perspective of the US healthcare payer. METHODS: A partitioned survival model was used to evaluate the cost-effectiveness of EVP compared to standard chemotherapy, incorporating 3 health states: progression-free survival (PFS), progressive disease, and death. The analysis was conducted from the perspective of a US healthcare payer (Veterans Affairs, VA) using a 21-day simulation cycle over a 30-year horizon. Survival data were derived from the EV-302 trial and reconstructed using standard parametric models as well as flexible parametric models. Costs and utility values were sourced from public databases and literature. Sensitivity and scenario analyses assessed the impact of key parameters and different subgroups, with price simulations identifying the threshold price for cost-effectiveness. Total costs (in US dollars), life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios were used as main outcomes. RESULTS: In the base-case analysis, the lifetime cost of EVP was $989,917, providing an effectiveness of 2.50 QALYs and 4.86 life years. In contrast, chemotherapy cost $166,397 with an effectiveness of 1.49 QALYs and 2.83 life years. The incremental cost-effectiveness ratio for EVP compared to chemotherapy was $814,875 per QALY, indicating it is not cost-effective at the $150,000 threshold. Sensitivity analyses highlighted that the utility for PFS and the pricing of Enfortumab vedotin (EV) significantly impacted cost-effectiveness. Probabilistic sensitivity analysis confirmed chemotherapy as the most cost-effective option across a willingness-to-pay range of $0 to $300,000. Price simulations suggested that EVP would become cost-effective compared to chemotherapy if the price of EV were reduced to $593 per 20 mg. Subgroup analysis showed that at its original price, EV was not cost-effective in any subgroup. However, reducing its price to 22 to 29% of the original made EVP economically viable for various subgroups. CONCLUSIONS: EVP is more effective than chemotherapy but not cost-effective from the perspective of the VA. To achieve cost-effectiveness, a price reduction for EV is necessary.