The nuclear protein Sam68 has been implicated in the oncogenesis and tumor growth. The aim of this study was to explore the clinical value of Sam68 in patients with non-small cell lung cancer (NSCLC).We examined Sam68 expression in 50 NSCLC tissues and matched adjacent noncancerous tissues by quantitative RT-PCR (qRT-PCR) and Western blotting. Furthermore, the Sam68 protein expression was analyzed by immunohistochemistry in 208 NSCLC samples. Kaplan-Meier method and multivariate Cox regression model were used to evaluate the prognostic value of nuclear Sam68 expression in NSCLC for disease survival.The expression of Sam68 was significantly elevated in NSCLC tissues as compared with adjacent non-cancerous tissues (P < 0.01). The high expression of Sam68 in NSCLC was significantly correlated with lymph node metastasis and tumor TNM stage. Kaplan-Meier survival analysis revealed that high expression of Sam68 correlated with poor prognosis of NSCLC patients (P < 0.01). Multivariate analysis showed that Sam68 expression was an independent prognostic marker for overall survival of NSCLC patients (HR 2.73, 95 % CI 1.549-4.315, P = 0.002).Our results suggest that high Sam68 expression predicts poor prognosis of NSCLC patients, and Sam68 may be potentially a prognostic biomarker for NSCLC.