Although the survival of lung cancer patients has improved significantly due to the development of early detective tools, lung cancer remains a leading cause of cancer-related death after curative surgery. So it is extremely important for cancer patients to predict early metastasis, especially pleural dissemination, the most frequent type of recurrence in patients after surgery. Based on a retrospective study of 86 curatively resected lung cancer patients (training set), we determined a cutoff value of NSE mRNA using receiver-operating characteristic curve. Then, we prospectively used this cutoff value to validate the risk of pleural recurrence in a new cohort of 81 lung cancer patients (validation set) between April 2009 and June 2010 by real-time reverse transcriptase-polymerase chain reaction. During the median 27 months of postoperative surveillance, 16 of the 81 patients died, and 9 of the 16 developed pleural metastases. Multivariate analysis with the Cox proportional hazards model showed that positive NSE mRNA was a significant independent risk factor with both overall survival and pleural recurrence-free survival (both P < 0.0001) as end points which were significantly worse in patients with positive NSE mRNA (P < 0.0001). These results indicate that quantitative NSE mRNA in pleural fluid is a reliable prognostic indicator of pleural recurrence in the clinical setting.