This multicenter retrospective study analyzed data from 1266 patients with advanced non-small cell lung cancer (NSCLC) across five leading hospitals in China. The aim was to evaluate survival outcomes and safety profiles of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The main outcomes included overall survival (OS) and progression-free survival (PFS), while the secondary endpoint was adverse events. Kaplan-Meier survival analysis, univariate and multivariate Cox regression modeling, and propensity score matching (PSM) analyses were performed to compare the real-world efficacies of PD-1 and PD-L1. Patients receiving PD-1 inhibitors had significantly longer median OS compared with those treated with PD-L1 inhibitors (28.2 versus [vs.] 24.6 months; hazard ratio [HR] 0.74 [95% confidence interval (CI) 0.59-0.93]; p = 0.0099), with consistent effects after PSM analysis (HR 0.70 [95% CI 0.12-0.91]; p = 0.005) and multivariable, adjusted Cox regression model with HR of 0.74 ([95% CI 0.59-0.93]; p = 0.01). Further analysis indicated that body mass index ≥ 24 kg/m2 (HR 0.72 [95% CI 0.75-0.93]; p = 0.014) and history of hypertension (HR 1.35 [95% CI 1.01-1.79]; p = 0.037) may interfere with the therapeutic effects of PD-1 with comparable safety profiles, which renewed personalized immunotherapy options for NSCLC patients in clinical settings.© 2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.