The aim of this study was to investigate the expression and prognostic significance of NEDD9 in pancreatic ductal adenocarcinoma (PDA). Expressional levels of NEDD9 mRNA and protein in paired pancreatic cancer lesions and adjacent noncancerous tissues were examined by quantitative real-time PCR and western blotting. NEDD9 expression was analyzed by immunohistochemistry in 106 patients with PDA. The correlations between NEDD9 immunostaining levels and clinicopathologic factors, as well as the follow-up data of patients, were analyzed statistically. NEDD9 protein and mRNA levels were elevated in pancreatic carcinoma lesions compared with the paired adjacent noncancerous tissues. A high level of expression of NEDD9 was significantly correlated with clinical staging (P < 0.001), lymph node metastasis (P < 0.001), and histological differentiation (P < 0.001). Patients with a higher NEDD9 expression had a significantly shorter survival time than those patients with lower NEDD9 expression. The multivariate analysis revealed that NEDD9 could serve as an independent factor of poor prognosis. Our finding indicates that NEDD9 could be used as prognostic molecular marker and therapeutic target for PDA.