The authors conducted a multicenter retrospective study on the outcome of programmed death-ligand 1 tumor proportion score≥50small cell lung cancer patients treated with first-line pembrolizumab according to the presence/absence of brain metastases. A total of 282 patients were included, of whom 56 had brain metastases that were treated with upfront local radiation therapy in 188.8.131.52P=0.48), respectively, while intracranial response rate and intracranial disease control rate were 67.55.0 respectively. The median time-to-treatment failure (TTF) and overall survival (OS) were 4.2 and 9.9 months versus 10.8 and 26.5 months for patients with and without brain metastases (P=0.06 and 0.05, respectively). Drug discontinuation rate due to treatment-related adverse events was 10.70.2 respectively. Multivariate analysis showed that baseline steroids was an independent predictor for a worse OS (Ptextless0.001), while performance status (PS)≥2 was an independent predictor for a poorer TTF (Ptextless0.001) and OS (Ptextless0.001). In patients with brain metastases, only PS ≥2 was predicted for a worse TTF (P=0.02) and OS (P=0.03). Pembrolizumab has activity against brain metastases from non-small cell lung cancers with programmed death-ligand 1≥50 and PS ≥2 seems to be the only factor associated with a worse outcome in patients with brain metastases.