Oncogenic human papillomaviruses (HPVs) have been detected in oral squamous cell carcinoma (SCC). HPV16 is the most frequently detected HPV type in oral SCC and is present in up to 22% of cases, either alone or in combination with other HPV types. HPV18 is present in up to 14% of cases. HPV16 and HPV18 are present together in approximately 6% of cases. However, HPV16 and 18 are also detected in normal oral mucosae (10% and 11% of subjects, respectively). These data suggest that high risk HPV infection may be a co-factor in oral carcinogenesis and that latent HPV infection of the oral mucosa is common. A role for HPV infection in oral carcinogenesis is supported by the ability of high risk HPVs to immortalize oral keratinocytes in vitro. Immortalization may involve (i) deactivation of pre-formed tumor-suppressor proteins by viral oncoproteins, (ii) blocking of tumor-suppressor gene transcription as a result of HPV oncogene insertion or (iii) stimulation of cellular oncogene transcription by the upstream insertion of HPV-derived transcription activating sequences. Hence, infection of oral keratinocytes with high risk HPV may be involved in the pathogenesis of some oral SCCs although the evidence implicating HPV in oral carcinogenesis is, at present, mainly circumstantial.