Purpose: Oral papillary squamous cell carcinoma (OPSCC) is a histologic variant of SCC with a growth pattern suggesting human papillomavirus (HPV) infection. The aim of this study was to investigate the presence of HPV genotypes in OPSCC. Materials and Methods: All cases with a histologic diagnosis of OPSCC from 1993 through 2008 were retrieved and confirmed. Immunohistochemical evaluation for the surrogate marker p16INK4A and HPV polymerase chain reaction were performed in tissue and DNA derived from formalin-fixed paraffin-embedded tissue. Results: Forty-four patients with confirmed OPSCC (mean age, 71.96 yr; female-to-male ratio, 1.75:1) comprised the study population. The most common site of involvement was the gingiva followed by the palate and buccal mucosa. Forty cases exhibited an invasive component, 1 was noninvasive, and in 3 cases invasion could not be confirmed owing to suboptimal thickness of the biopsy. Paraffin tissue blocks were available in 41 cases. Twenty-three cases (56.1%) exhibited positive p16INK4A staining, which was primarily weak to moderate with a generally focal pattern. Polymerase chain reaction assays were negative for HPV DNA in all cases. Conclusions: In this study, there was a clinical predilection of OPSCC in older women, with most cases occurring in the masticatory mucosa. Weak to moderate and focal p16INK4A staining was appreciated in contrast to reported staining properties in genital and oropharyngeal PSCC. Failure of the polymerase chain reaction assay to exhibit transcriptionally active HPV genotypes suggests that HPV is not associated with OPSCC tumorigenesis.