The identification of prognostic and predictive biomarkers for high-programmed cell death-ligand 1 (PD-L1) advanced non-small cell lung cancer (aNSCLC) treated with first-line pembrolizumab could support the decision-making about possible combination therapies. To explore the baseline neutrophil-to-lymphocyte ratio (NLR) with the possible addition of PD-L1 tumour proportion score (TPS) level or lactate dehydrogenase (LDH) as possible prognostic biomarkers by a multicenter retrospective exploratory analysis aiming at identifying favourable-risk patients. Baseline NLR was available for all 132 high PD-L1 aNSCLC patients, PD-L1 level and LDH for 81 (61 and 85 (64 patients, respectively. NLR, PD-L1 and LDH cut-offs by receiver operating characteristic (ROC) curves were 4.9, 77.568.5, respectively. Seventy-one patients (54 had NLR textless5; 25 out of 81 NLR textless5 (31 had PD-L1 textgreater80 26 out of 85 (31 NLR textless5 and normal LDH (nLDH). Median follow-up was 16.3 months. As compared to NLR textgreater5, significantly better 2-year overall survival (OS) and progression-free survival (PFS) were observed with NLR textless5 [621 P=0.005, hazard ratio (HR) 0.45, and median of 12.0 vs. 5.7 months, P=0.01, HR 0.56, respectively], NLR textless5 + PD-L1 textgreater8081 P=0.006, HR 0.20 and median of 14.7, P=0.03, HR 0.44, respectively), and NLR textless5 + nLDH (74 P=0.009, HR 0.25 and median of 14.7, P=0.02, HR 0.40, respectively). NLR textless5 and NLR textless5 + nLDH significantly associated with PD (P=0.008 and P=0.025, respectively) but not response rate (RR) (P=0.09 and P=0.07, respectively); NLR textless5 + PD-L1 textgreater80P=0.03) and PD (P=0.02). NLR textless5 ± PD-L1 textgreater80to-assess tools to identify high PD-L1 aNSCLC patients with favourable outcome following first-line pembrolizumab monotherapy.