Background: Pembrolizumab, a humanized immunoglobulin monoclonal antibody directed against the programmed cell death 1 receptor, demonstrated robust efficacy and a manageable safety profile across multiple tumor types in clinical trials. Aim: To investigate the efficacy and safety of first-line pembrolizumab for patients with non-small cell lung cancers (NSCLCs) in clinical practice. Methods: In this observational monocentric retrospective study, 38 patients with PD-L1 >50% were enrolled between November 2017 and November 2018. Results: The global median overall survival was 11.08 months (95% confidence interval [CI], 5.98-not reached) and the global median progression-free survival was 6 months (95% CI, 3-not reached). In the univariate analysis, clinical performance status score and the development of immune-related adverse events were the only 2 clinical factors significantly correlated with overall survival. Conclusion: The results of the present study suggest that pembrolizumab seems less effective in the real-life population than in the pivotal clinical trials in patients with NSCLC but remains an effective treatment option for patients with NSCLC. Longer follow-up is needed.