This preliminary study evaluated the expression of human papilloma virus （HPV） 16, HPV18, and p16 as possible biomarkers to distinguish normal oral epithelium （NOE） from oral epithelial dysplasia （OED） and oral intraepithelial neoplasia （OIN）. Subjects comprised 150 cases including 41 with OED, 30 with OIN, and 67 with oral squamous cell carcinoma （OSCC）. NOE was also taken from 12 healthy participants. Staining indices of HPV16, HPV18, and p16 were immunohistochemically examined using paraffin-embedded specimens. A statistically significant difference was seen in the expression of HPV18 and p16 in OED/OIN compared with NOE and OSCC. Furthermore, regression tree analysis of independent variables, including p16 and HPV18 expression and the participants’ age, was performed to distinguish NOE from OED/OIN. In conclusion, this preliminary study demonstrated that p16 and HPV18 expression and participants’ age （60 years） can be used to distinguish NOE from OED/OIN.