In small-cell lung cancer (SCLC), the role of chemotherapy and radiotherapy is well established. Large-cell neuroendocrine carcinoma (LCNEC) shares several clinicopathological features with SCLC, but its optimal therapy is not defined. We evaluated clinical response and survival outcomes of advanced LCNEC treated in first-line therapy compared with SCLC.72 patients with stage III–IV LCNEC (n=28) and extensive-stage SCLC (ES-SCLC) (n=44) received cisplatin–etoposide with/without thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI).Comparing LCNEC with SCLC, we observed similar response rates (64.2%versus59.1%), disease control rates (82.1%versus88.6%), progression-free survival (mPFS) (7.4versus6.1 months) and overall survival (mOS) (10.4versus10.9 months). TRT and PCI in both histologies showed a benefit in mOS (34versus7.8 months and 34versus8.6 months, both p=0.0001). LCNEC patients receiving TRT showed an improvement in mPFS and mOS (12.5versus5 months, p=0.02 and 28.3versus5 months, p=0.004), similarly to ES-SCLC. PCI in LCNEC showed an increase in mPFS (20.5versus6.4 months, p=0.09) and mOS (33.4versus8.6 months, p=0.05), as in ES-SCLC.Advanced LCNEC treated with SCLC first-line therapy has a similar clinical response and survival outcomes to ES-SCLC.