Large cell neuroendocrine cancer (LCNEC) of the lung exhibits morphological and immunohistochemical characteristics of both neuroendocrine and large cell carcinomas. No defined optimal therapy has been described for this subset of patients and the question of whether these patients should be treated with non-small cell lung cancer (NSCLC) treatment protocols, according to the National Comprehensive Cancer Network (NCCN) guidelines, or with small cell lung cancer (SCLC) due to histological and clinical similarities is still uncertain. We conducted a retrospective review of patients identified with diagnosis of LCNEC of the lung at the University of Cincinnati Cancer Center from the year 2002 to 2012 to determine which treatment approach resulted in improved outcomes in this rare category of disease. Patients who received chemotherapy whether NSCLC (group A) or SCLC (group B) protocols did not show significant changes in OS (P=0.911). Meanwhile, patients who underwent surgery (group C) had better OS compared to groups A and B (P= 0.027 and 0.024, respectively). This analysis reveals that outcomes for SCLC or NSCLC treatment strategies in LCNEC patients did not result in survival advantages and future research should be addressing it as a separate entity.