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Objective: The aim of our study was to investigate the prevalence and clinical relevance of neuroendocrine (NE) differentiation in lung adenocarcinoma. Methods: Eighty-six adenocarcinoma paraffin-embedded specimens and cases which were followed up completely for 3 years, were obtained from 86 patients (35 men and 51 women) who underwent surgical resection for pathologically supported adenocarcinoma in the Cancer Hospital of Tianjin Medical University, from June 2005 to December 2006. Immunohistochemical EnVision two-step method was used to detect the expression of neuron-specific enolase (NSE), synaptophysin (SYN) and chromogranin A (CGA). All data were analyzed using SPSS statistics software and Kaplan-Meier survival curves were constructed, meanwhile, we conducted a Log-rank test. Results: All patients with lung adenocarcinoma, 35 cases with NE differentiation (40.7%). The statistical analysis showed that the positive rate of NE differentiation in lung adenocarcinoma was significantly associated with cancer recurrence and histological differentiation. In addition, CGA, NSE and SYN positive rates were 27.9%, 50.0%, 43.0%, respectively. A statistically significant difference was found between positive expression of SYN and other clinicopathological parameters, such as pathological type, histological differentiation, lymph node metastasis, postoperative recurrence and 3-year survival rate (P = 0.001) and so on. Conclusion: NE differentiation can be used as a metastatic potentially indicator of biological behavior of lung adenocarcinoma, and combined detection of NSE and SYN markers may be recommended to examine NE differentiation of lung adenocarcinoma. Positive expression of SYN indicates poor prognosis.