Astrocyte elevated gene 1 (AEG-1), a novel oncoprotein, has been implicated in oncogenesis and cancer progression in various types of human cancers. The clinical significance and biological role of AEG-1 in non-small cell lung cancer (NSCLC), however, remain unclear. In the present study, we found that the expression of AEG-1 was markedly up-regulated in NSCLC cell lines and NSCLC tissues at the level of both transcription and translation. Ectopically expressed AEG-1 enhanced the migratory and invasive abilities of NSCLC cells, whereas knockdown of endogenous AEG-1 by specific shRNAs significantly inhibited these abilities. The function of AEG-1 on metastasis modulation was associated with the activation of the PI3K-Akt and NF-kappaB signalling pathways. Furthermore, we showed high expression of AEG-1 in 99/200 (49.5%) paraffin-embedded archival NSCLC specimens. Moreover, statistical analysis displayed a significant correlation in AEG-1 expression with the clinical stage (p < 0.001), T classification (p = 0.001), N classification (p = 0.015), distant metastasis (p = 0.004) and differentiation (p = 0.027). Patients with higher AEG-1 expression had an overall shorter survival time, whereas patients with lower expression of AEG-1 had a better survival time. Multivariate analysis suggested that AEG-1 expression might be an independent prognostic indicator for the survival of NSCLC patients. Taken together, our results suggest that elevated expression of AEG-1 plays an important role in the aggressiveness of NSCLC, leading to a poor clinical outcome.