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Background: In the first-line treatment of elderly patients with advanced-stage non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression (tumor proportion score ≥ 50%), this study aimed to determine whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) should be selected., Methods: We performed a retrospective multicenter study (sub-analysis of the HOT/NJLCG2001 trial) of 299 patients with NSCLC with high PD-L1 expression who received MONO or COMB as the first-line treatment between December 2018 and January 2020. We selected patients aged 75 years and older and assessed the clinical efficacy and toxicity., Results: In total, 81 (median age: 79 years) and 19 (median age: 76 years) patients received MONO and COMB, respectively. Twenty patients with a performance status (PS) score of 2-3 were enrolled in the MONO group. The median progression-free survival (PFS) was 7.8 and 8.9 months in the MONO and COMB groups, respectively. The median overall survival (OS) was 14.6 and 20.3 months, and the 2-year survival rates were 38.8 and 49.9%, respectively. Furthermore, 29.6% and 26.3% of patients discontinued treatment due to adverse events, respectively. In MONO, patients with PS 0-1 had a longer PFS (10.5 months) and OS (21.7 months) than those with PS 2-3 (0.7 and 1.6 months, respectively)., Conclusion: Some elderly patients with NSCLC and high PD-L1 expression might benefit from COMB; however, MONO is considered the preferred treatment. MONO may not be an effective or feasible treatment for patients with PS 2-3, even with high PD-L1 expression., (© The Author(s) 2024. Published by Oxford University Press.)