Background <p>Although pembrolizumab plus chemotherapy (Pembro + Chemo) is the recommended first-line therapy for advanced esophageal cancer, it remains unclear whether it is more cost-effective than chemotherapy (Chemo). We evaluated the cost-effectiveness of Pembro + Chemo versus Chemo from a Japanese healthcare payer perspective.</p> Methods <p>A partitioned survival analysis model was developed to predict costs and quality-adjusted life years (QALY) for Pembro + Chemo and Chemo. The model parameters were based on a previous randomized controlled trial and a nationwide administrative database in Japan. The incremental cost-effectiveness ratio (ICER) of Pembro + Chemo compared with Chemo was estimated. A subgroup analysis on the level of PD-L1 Combined Positive Score (CPS) ≥ 10 was also conducted. Additionally, one-way deterministic sensitivity analysis and probabilistic sensitivity analysis with Monte Carlo simulations (5,000 simulations) were conducted.</p> Results <p>The ICER of Pembro + Chemo over Chemo was estimated at USD 176,479 per QALY. The subgroup analysis for patients with PD-L1 CPS ≥ 10 showed an ICER of USD 126,862 per QALY. One-way deterministic sensitivity analysis demonstrated that the ICER remained above the willingness-to-pay threshold of USD 50,000–100,000 per QALY in all scenarios, with the utility of progression-free survival in the Pembro + Chemo group having the greatest influence on the ICER. Probabilistic sensitivity analysis showed that the probability of Pembro + Chemo being cost-effective was 0% at the willingness-to-pay threshold.</p> Conclusion <p>The addition of pembrolizumab to chemotherapy was not cost-effective in treating advanced esophageal cancer in Japan.</p>