Skp2 putatively plays a critical role in regulating cell cycle progression. A high level of Skp2 expression is observed in a variety of cancer. No previous report describes the prognostic value of Skp2 mRNA in non-small cell lung cancer (NSCLC). Therefore, the purpose of this study was to examine overexpression of Skp2 mRNA in NSCLC and identify the association of Skp2 expression level with patient survival. We investigated Skp2 expression in 79 patients with NSCLC by means of reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. The Skp2 expression was significantly associated with tumor status, lymph node metastasis, stage, vascular invasion, histology and Skp2 protein. With regard to prognosis, the overall and stage I survival rates for patients in the high Skp2 mRNA group were significantly poorer when compared with the low Skp2 mRNA group. Furthermore, expression of Skp2 mRNA was an independent predictor of prognosis by multivariate analysis. Skp2 expression might play an important role in the development and progression in NSCLC and Skp2 gene expression can serve as a useful prognostic marker in NSCLC patients.