Human papillomavirus (HPV) is a known risk factor for certain head and neck cancers. Tumors of head and neck region are heterogeneous in nature with different incidences, mortalities and prognosis for different subsites. Unlike oropharynx, where data favors inclusion of HPV status in disease management, role of HPV in oral cavity squamous cell carcinoma (OSCC) is not well understood. The prevalence of HPV in OSCC, although considered lower than oropharynx, vary greatly based on the choice of HPV assay and patient geography. Additionally, data on HPV positive OSCC is scarce and there is less agreement on HPV being a good prognostic factor in OSCC. Here with 153 OSCC patients, using multiple analytes and assays, we show that a high prevalence (33-58%) of HPV16/18 DNA did not correlate with an equally high prevalence of transcriptionally active viral genomes (E6/E7 RNA prevalence 15%) in tumors. Only 6% of the tumors showed the presence of both HPV DNA and HPV16/18 E6/E7 RNA and none with both p16 and HPV RNA. Most tumors with relatively high-copy HPV DNA and/or HPV E6/E7 mRMA, but not with HPV DNA alone (irrespective of copy number), were wild type for TP53 and CASP8 genes. In our study, p16 protein, HPV DNA and E6/E7 RNA, either alone or in combinations, did not correlate with patient survival. Using genome-wide methylation data, 9 HPV-associated genes stratified the HPV +ve from the HPV negative tumor groups with high confidence (p<0.008) when relatively high-copy number of HPV DNA and/or HPV E6/E7 RNA were considered to define HPV positivity and not HPV DNA alone irrespective of their copy number (p<0.2). Taken together, we conclude that tests measuring HPV DNA alone without viral load and/or viral RNA may not be a true measures of HPV infection in oral cavity tumors and therefore are not informative.