Oral papillary squamous cell carcinoma (PSCC) is a recognized but rare variant of oral squamous cell carcinoma (SCC). Its unique papillary exophytic growth pattern has brought about speculation as to whether human papillomavirus (HPV) is implicated in its growth and malignant transformation and whether the cell cycle is thereby deregulated. The prevalence of HPV was investigated in formalin-fixed paraffin embedded tissue of 33 oral PSCCs and 10 conventional oral SCCs using PCR with HPV consensus primers GP5+/GP6+. The expression of the cell cycle proteins p16, cyclin D1 and Ki-67 were examined using immunohistochemistry. HPV was identified in 4 of 33 oral PSCC cases (12%) and 1 of 10 conventional oral SCC cases (10%). Strong nuclear staining for p16 was detected in 4 of the 5 HPV positive cases. p16 nuclear staining was also observed in 1 specimen in which HPV was not detected. There was a statistically significant association of HPV status to p16 protein expression. HPV infection is rarely detected in oral PSCCs and may be implicated infrequently in their carcinogenesis. The prevalence of HPV infection in oral PSCC is similar to that of conventional oral SCC. p16 is overexpressed in SCCs harbouring HPV and may be useful as an adjunctive marker for HPV status.