e17018 Background: Polycomb group proteins are transcriptional repressors that silence specific sets of genes through chromatin modification. The enhancer of zeste homolog 2 (EZH2), considered a member of the polycomb group proteins, is overexpressed in aggressive forms of several malignancies. However, the role of EZH2 expression in head and neck cancer has not yet been fully determined. This study was conducted to investigate the clinical value of EZH2 expression in head and neck cancer and its correlation with Ki-67 and p53 expression. Methods: Expression of EZH2, Ki-67, and p53 was determined by immunohistochemical staining of tissue microarrays from specimens of 138 cases of head and neck squamous cell carcinoma. Results: High EZH2 expression was observed in 51.5%. 44.2% were positive for p53. The percentage of Ki-67 staining was significantly greater in the EZH2 positive group (12.37 ± 8.51) than in the EZH2 negative group (4.73 ± 6.06, p < 0.001). EZH2 expression was significantly correlated with p53 expression (p = 0.003) and smoking history (p = 0.021). However, we found no significant differences in other clinicopathological parameters (age, sex, primary tumor size, and lymph node metastasis) and survival between the EZH2 positive and negative groups. Conclusions: These results suggest that high EZH2 expression may be associated with tumor cell proliferation and cell cycle regulation in head and neck cancer. No significant financial relationships to disclose.