Reduced expression of p27^Kip1, a cyclin-dependent kinase (Cdk) inhibitor, is frequently found in various cancers, including oral squamous cell carcinoma (OSCC), and is attributable to an enhancement of its degradation. Skp2, an F-box protein necessary for DNA replication, is required for the ubiquitinylation and subsequent degradation of p27^Kip1. In the present study, we examined the expression of Skp2 and its correlation with the expression of p27^Kip1 protein or p27^Kip1 degradation in OSCC. Using immunohistochemistry, we found that high expression of Skp2 was present in 49% of OSCCs and only 20% of epithelial dysplasias. Significantly, high expression of Skp2 was correlated with poor prognosis of OSCC patients. We also found an inverse correlation between the expression of Skp2 and p27 by immunohistochemical analysis. A similar correlation was observed in OSCC cell lines and OSCC tissues by Western blot analysis. Interestingly, OSCC tissues with Skp2 expression had high p27^Kip1 degradation activity. These findings indicate that (a) Skp2 may play an important role for the development of OSCC, (b) Skp2 can be a novel target for OSCC treatment as well as a strong prognostic marker, and (c) the reduction in p27^Kip1 protein may be brought about by enhancement of its degradation mediated by increased levels of Skp2 protein.