Background：The phase III clinical trial Keynote-604 indicated that pembrolizumab plus chemotherapy could generate clinical benefits in Extensive-Stage Small-Cell Lung Cancer (ES-SCLC). We aim to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy as the first-line treatment of ES-SCLC from the United States (US) payers’ perspective.Methods: A synthetical Markov model was used to evaluate cost and effectiveness of pembrolizumab plus platinum-etoposide (EP) versus EP in first-line therapy for ES-SCLC from the data of Keynote-604. Lifetime costs life-years (LYs), quality adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed. In addition, We also considered subgroup cost-effectiveness.Results: Pembrolizumab plus EP resulted in additional 0.18 QALYs (0.32 LYs) and corresponding incremental costs $113,625, resulting an ICER of $647,509 per QALY versus EP. The most influential factor in this model was the cost of pembrolizumab. Probabilistic sensitivity analysis showed there was 0% probability that pembrolizumab combination chemotherapy was cost-effective at willingness-to-pay (WTP) values of $150,000 per QALY in the US. The results of subgroup probabilistic sensitivity analyses suggested that all subgroups were not cost-effective.Conclusion: From the perspective of the US payer, pembrolizumab plus EP is not a cost-effective option as first-line treatment for patients with ES-SCLC at a WTP threshold of $150,000 per QALY.