BackgroundImmune checkpoint inhibitors (ICI)-based combination strategies have improved the survival outcomes in advanced non-small cell lung cancers; however, data regarding their efficacy remains limited for uncommon histological types, including large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC).MethodsWe retrospectively analyzed a total of 60 patients with advanced LCC and LCNEC – 37 treatment-naïve and 23 pre-treated – who received pembrolizumab with or without chemotherapy. Treatment and survival outcomes were analyzed.ResultsOf the 37 treatment-naïve patients who received first-line pembrolizumab combined with chemotherapy, the 27 patients with LCC had an overall response rate (ORR) of 44.4% (12/27) and a disease control rate (DCR) of 88.9% (24/27); whereas 10 patients with LCNEC had an ORR of 70% (7/10) and DCR of 90% (9/10). The median progression-free survival (mPFS) was 7.0 months (95% confidence intervals [CI]: 2.2–11.8) and median overall survival (mOS) was 24.0 months (95%CI: 0.0–50.1) for first-line pembrolizumab plus chemotherapy of LCC (n= 27), whereas mPFS was 5.5 months (95%CI: 2.3–8.7) and mOS was 13.0 months (95%CI: 11.0–15.0) for first-line pembrolizumab plus chemotherapy of LCNEC (n= 10). Of the 23 pre-treated patients who received subsequent-line pembrolizumab with or without chemotherapy, mPFS was 2.0 months (95% CI: 0.6–3.4) and mOS was 4.5 months (95% CI: 0.0–9.0) for LCC and mPFS was 3.8 months (95% CI: 0.0–7.6) and mOS was not reached for LCNEC.ConclusionOur study provides real-world clinical evidence of the anti-tumor activity of pembrolizumab plus chemotherapy in advanced LCC and LCNEC, indicating that this regimen could serve as a treatment option, particularly as first-line therapy, for improving the survival outcomes of patients with these rare histological subtypes of lung cancer.Trial registrationNCT05023837(ESPORTA, 27/08/2021).Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-023-10952-w.