Summary Histone deacetylase 2 (HDAC2) has been implicated in the development and progression of several human tumors. We immunohistochemically examined the expression of HDAC2 protein in 20 cases of oral epithelial dysplasia (OED) and 93 cases of oral squamous cell carcinoma (OSCC). Positive HDAC2 nuclear staining was observed in 80 of the 93 (86.02%) cases of SCC and 11 of the 20 (55%) cases of ED. The labeling index (LI) for HDAC2 nuclear staining increased significantly from ED (25.8 ± 26.5%) to SCCs (59.8 ± 28.5%) ( p < 0.001). No significant correlation was found between the HDAC2 expression level and patient’s age, sex, oral habits in oral SCC patients. However, cancer with advanced stage, larger tumor size, or positive lymph node metastasis had higher level of HDAC2 protein expression. Kaplan–Meier curves showed oral SCC patients with high HDAC2 expression (LI > 50%), advanced stage, larger tumor size, or positive lymph node metastasis had significantly shorter overall survival ( p = 0.0158, 0.0267, 0.0029 and 0.02514, respectively by log-rank test) than others. The results of this study show for the first time that overexpression of the HDAC protein is a frequent event in oral cancer and could be used as a prognostic factor in oral SCC.