BACKGROUND: Patients with advanced pulmonary large-cell neuroendocrine carcinoma (LCNEC) have a progressive clinical course and poor prognosis, and effective treatment options remain limited. This study assessed the efficacy and safety of immunotherapy plus chemotherapy for advanced LCNEC. METHODS: We retrospectively collected medical records of patients with advanced LCNEC who attended Shandong Cancer Hospital from January 2018 to December 2022. Patients were divided into two groups based on their previous treatment regimen: immunotherapy plus chemotherapy and chemotherapy alone. Kaplan-Meier survival curves and Cox regression models were used to evaluate the clinical efficacy of different treatment regimens. RESULTS: The median follow-up was 29.33 months (95% confidence interval [CI]: 24.04-not reached). The median overall survival (OS) was 15.01 months (95% CI: 11.99-26.31) and 7.19 months (95% CI: 5.15-10.57) in the immunotherapy plus chemotherapy and chemotherapy groups, respectively (P = 0.001). Following propensity score matching, the median OS was 17.41 months (95% CI: 11.99-29.20) and 5.88 months (95% CI: 4.50-11.53) in the immunotherapy plus chemotherapy and chemotherapy groups, respectively. The median progression-free survival was 6.70 months (95% CI: 5.48-13.27) and 3.12 months (95% CI: 2.52-4.20) in the immunotherapy plus chemotherapy and chemotherapy groups, respectively. We also found that increasing age may contribute to poorer prognosis in patients with advanced LCNEC (P <
0.05). CONCLUSIONS: Immunotherapy plus chemotherapy significantly improved OS compared with chemotherapy in LCNEC, with a tolerable safety profile without life-threatening adverse events. Immunotherapy plus chemotherapy may be an effective treatment option for patients with advanced LCNEC.