Abstract Background There is controversy regarding palliative chemotherapy for large cell neuroendocrine carcinoma (LCNEC). We evaluated whether advanced LCNEC should be treated similarly to small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Patients and methods The clinical reports and tumor specimens of 45 consecutive patients who were diagnosed with advanced LCNEC were reviewed. They were divided into SCLC ( n = 11) and NSCLC regimen groups ( n = 34) according to first-line chemotherapeutic regimens. Results Most patients were male (96%) and smokers (93%) with a median age of 64 years. Neuroendocrine differentiation was established in 42 (93%) tumors by immunohistochemical analyses. Regarding the efficacy of first-line chemotherapy in the SCLC and NSCLC regimen groups, the response rates were 73% and 50% ( P = 0.19), and the median progression-free survival times were 6.1 and 4.9 months ( P = 0.41), respectively. The difference in overall survival between the two treatment groups was 7.3 months (16.5 vs. 9.2 months, P = 0.10). There was also a considerable difference in the type and efficacy of salvage chemotherapeutic regimens between the two groups: salvage regimens with irinotecan, platinum, or taxanes were commonly used with relatively high objective responses in the SCLC regimen group, whereas frequently used agents in the NSCLC regimen group such as pemetrexed, gefitinib, or erlotinib were associated with no objective response. Conclusion Regarding palliative chemotherapy for advanced LCNEC, treatment similar to SCLC is more appropriate than NSCLC.