IntroductionPembrolizumab alone (IO-mono) or in combination with platinum-based chemotherapy (CT-IO) is first-line standard of care for advanced non-small cell lung cancer (NSCLC) patients with PD-L1 ≥ 50%. This retrospective multicentre study assessed real-world use and efficacy of both strategies.MethodsPatients with advanced NSCLC PD-L1 ≥ 50% from eight hospitals who had received at least one cycle of IO-mono or CT-IO were included. Overall survival (OS) and real-word progression-free-survival were estimated using Kaplan–Meier methodology. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs, and a Cox model with inverse propensity treatment weighting was carried out.ResultsAmong the 243 patients included, 141 (58%) received IO-mono and 102 (42%) CT-IO. Younger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. With a median follow-up of 11.5 months (95% CI 10.4–13.3), median OS was not reached, but no difference was observed between groups (p= 0.51). Early deaths at 12 weeks were 11% (95% CI 4.6–16.9) and 15.2% (95% CI 9.0–20.9) in CT-IO and IO groups (p= 0.32). After adjustment for age, gender, performance status, histology, brain metastases, liver metastases and tobacco status, no statistically significant difference was found for OS between groups, neither in the multivariate adjusted model [HR 1.07 (95% CI 0.61–1.86),p= 0.8] nor in propensity adjusted analysis [HR 0.99 (95% CI 0.60–1.65),p= 0.99]. Male gender (HR 2.01,p= 0.01) and PS ≥ 2 (HR 3.28,p< 0.001) were found to be negative independent predictive factors for OS.ConclusionYounger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. However, sparing the chemotherapy in first-line does not appear to impact survival outcomes, even regarding early deaths.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-022-03359-2.