Background: Oral leukoplakia (OL) is a potentially malignant oral mucosal disorder. A casual association between OL, oral squamous cell carcinoma (OSCC) and human papillomavirus (HPV) infection has been suggested, but no conclusive evidence has been presented. p16, a tumoursuppressor protein, is used as a surrogate marker for HPV infection. The aim of this study was to investigate how overexpression of p16 correlates with HPV infection in OL and in OSCC. Patients and Methods: Seventy-four patients with OL and 13 with OSCC with p16 overexpressed, were analyzed by immunohistochemistry visualizing p16 and a real-time polymerase chain reaction (