Human DEK gene on chromosome 6p encodes a 43kD nuclear phospoprotein that was originally identified as part of a fusion protein found in a subset of acute myeloid leukemia carrying a t(6;9) translocation. Although DEK upregulation has been described in a number of human malignancies and was significantly associated with high histologic grade, lymph node metastasis and/or advanced clinical stage, no previous report has evaluated the expression of DEK protein and its clinical significance in oral squamous cell carcinoma (OSCC). Our aims were to determine DEK expression in tissue samples of normal oral mucosa and OSCC by immunohistochemistry, to analyze the correlation between DEK expression and clinicopathological parameters, and to evaluate the value of DEK as a prognostic marker for patient’s survival. Ten normal oral mucosa, 10 epithelial dysplasia, and 60 OSCC samples were studied by immunohistochemistry. DEK expression tended to increase through the full thickness of epithelium in the dysplastic mucosa when compared with those in normal oral mucosa. High expression of DEK protein (score ≥ 2) was found in 68.3% of OSCC cases. Statistical analysis revealed that DEK overexpression in OSCC was positively correlated with high histologic grade (p=0.001), lymph node metastasis (p=0.003), and advanced clinical stage (p=0.039). In the Kaplan-Meier survival analysis, DEK overexpression was significantly associated with decreased overall survival in patients with OSCC (p=0.019). Our results suggest that DEK overexpression may be a reliable marker to predict the clinical outcome in OSCC.