Both pembrolizumab (P) and combination of pembrolizumab with platinum-based chemotherapy (PCT) represent standard 1-line options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS) ≥50%. The two strategies have never been compared in a randomized trial. 256 consecutive patients with -wild-type PD-L1 TPS ≥50% aNSCLC receiving P (group P, n = 203) or PCT (group PCT, n = 53) as a 1-line treatment were identified in the electronic databases of 4 Israeli cancer centers. Time-to-treatment discontinuation (TTD) and overall survival (OS) were assessed. Baseline characteristics were well balanced, except for age and ECOG PS differences in favor of group PCT. Median (m)TTD was 4.9 months (mo) (95% CI, 3.1-7.6) 8.0mo (95% CI, 4.7-15.6) (-0.09), mOS was 12.5mo (95% CI, 9.8-16.4) 20.4mo (95% CI, 10.8-NR) (-0.08), with P and PCT, respectively. In the propensity score matching analysis (n = 106; 53 patients in each group matched for age, sex and ECOG PS), mTTD was 7.9mo (95% CI, 2.8-12.7) 8.0mo (95% CI, 4.7-15.6) (-0.41), and mOS was 13.3mo (95% CI, 6.8-20.3) 20.4mo (95% CI, 10.8-NR) (-0.18), with P and PCT, respectively. Among various subgroups of patients examined, only in females (n = 86) mOS differed significantly between treatments (10.2mo (95% CI, 6.8-17.2) with P NR (95% CI, 11.4-NR) with PCT; -0.02). In the real-world setting, no statistically significant differences in long-term outcomes with P PCT were observed; a prospective randomized trial addressing the comparative efficacy of P and PCT in different patient subgroups is highly anticipated.: