BACKGROUND: The effectiveness of adding pembrolizumab to chemotherapy improve outcomes in newly diagnosed metastatic non-small-cell lung cancer (NSCLC). We aimed to evaluate the economic outcomes of first-line treatment by adding pembrolizumab to chemotherapy with and without the use of PD-L1 testing for patient selection. METHODS: A decision-analytic model was adopted to project the disease course of newly diagnosed metastatic nonsquamous and squamous NSCLC without EGFR or ALK mutations. The efficacy and toxicity data were gathered from the KEYNOTE-189 and KEYNOTE-407 trials. Transition probabilities were estimated from the reported survival probabilities in each group. Cost and health preference data were derived from published economic evaluations. The incremental cost-effectiveness ratio (ICER) was measured, and subgroup, one-way and probabilistic sensitivity analyses (PSA) were performed for exploring the model uncertainties. RESULTS: In the US context, pembrolizumab plus chemotherapy is projected to increase quality-adjusted-life year (QALY) by 1.168 and 0.988 in comparison with chemotherapy and the ICERs were $122,248 and $121,375/QALY in the whole nonsquamous and squamous patients with unconfirmed PD-L1 tumor proportion scores (TPS), respectively. After the selection of patients by PD-L1 TPS by PD-L1 testing, the ICERs of adding pembrolizumab treatment for patients with confirmed PD-L1 TPS >1% and ≥50% were $143,282 and $127,661/QALY in nonsquamous disease, and $131,495 and $121,554/QALY in squamous disease, respectively. The ICERs of adding pembrolizumab treatment for Chinese patients were higher than $40,000/QALY regardless of the histology and TPS subgroups, which highly exceed the willingness-to-pay threshold of $29,196/QALY (three times of per capita gross domestic product of China in 2018) in China. CONCLUSIONS: Pembrolizumab plus chemotherapy as first-line treatment for untreated metastatic NSCLC without EGFR or ALK mutations is a cost-effective option regardless of PD-L1 expression status in the US context, and not cost-effective in the Chinese context. However, PD-L1 categories-directed pembrolizumab could not increase the cost-effectiveness of immunotherapy.