OBJECTIVES: This study aimed to assess the cost-effectiveness of pembrolizumab monotherapy compared with chemotherapy as first-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with different tumor proportion scores (TPS), from perspectives of payers in China. MATERIALS AND METHODS: Basic information was derived from the KEYNOTE-042 trial. A Markov model was developed to simulate the process of NSCLC. Model inputs were based on published clinical trials and previous literatures. Costs were calculated from perspectives of payers in China. Sensitivity analyses were conducted to explore the impact of uncertainty. RESULTS: Treatment with pembrolizumab monotherapy for patients with high TPS (≥50%) was estimated to increase costs by $65,322 compared with chemotherapy, with a gain of 1.79 quality adjusted life years (QALYs) for an incremental cost-effectiveness ratio (ICER) of $36,493 per QALY. For patient population with TPS ≥ 20%, the ICER was $42,311 per QALY, while the corresponding ICER was $39,404 per QALY for patients with TPS ≥ 1%. Sensitive analyses for three different TPS populations were similar, which indicated the cost of PFS state in pembrolizumab arm and the price of pembrolizumab were the most influential factors in our study. CONCLUSION: ICERs yield by pembrolizumab monotherapy among different TPS populations were beyond the threshold we set, three times of the Gross Domestic Product per Capita of China in 2018 ($26,508/QALY). It is not a cost effective choice compared with standard chemotherapy for patients with locally advanced or metastatic NSCLC from the perspective of Chinese payer, regardless of TPS. Deeper discount of its current price would make pembrolizumab a preferable choice.