BACKGROUND AND OBJECTIVE: In Japan, indications for nivolumab have been expanded to include the combination therapy with ipilimumab in various cancers. This study aimed to evaluate the cost-effectiveness of combination therapy of nivolumab plus ipilimumab (NIV + IPI) for patients with advanced non-small-cell lung cancer (NSCLC), comparing it with platinum-doublet chemotherapy in Japanese settings. METHODS: A partitioned survival model was developed to predict costs and quality-adjusted life-years (QALYs) in a NIV + IPI arm and a chemotherapy arm. Data on overall survival and progression-free survival were derived from the CheckMate 227 trial. Cost estimates were based on a Japanese healthcare system perspective using real-world data from the JMDC claims database. Utilities were derived from published sources outside Japan. The incremental cost-effectiveness ratio (ICER) of NIV + IPI therapy compared with chemotherapy was estimated. A scenario analysis on the level of programmed death-ligand 1 (PD-L1) expression was conducted. In addition, sensitivity analyses were performed to assess the uncertainty in parameter settings. RESULTS: Compared with chemotherapy, NIV + IPI therapy incurred an additional cost of USD102,623 and conferred an additional 1.007 QALY, which resulted in an ICER of USD101,950/QALY gained. Contrary to prior expectations, the ICER of patients with a PD-L1 expression level ≥ 1% was higher than that of patients with a PD-L1 expression level < 1% (USD145,868/QALY and USD127,737/QALY, respectively). Sensitivity analyses showed a relatively robust result with the ICERs remaining higher than a Japanese price adjustment threshold of USD75,000/QALY with a few exceptions. CONCLUSIONS: The combination of NIV + IPI as first-line therapy would not be cost effective under a willingness-to-pay threshold of USD75,000/QALY from the perspective of the Japanese healthcare system.