Infection by high-risk human papillomaviruses (HPVs) and Epstein-Barr virus (EBV) are very frequent in the adult human population, and have been associated with several human carcinomas, especially oral cancers. However, a small number of studies have examined the association between high-risk HPV and EBV in the progression of human oral cancers. Currently, the role of high-risk HPV and EBV co-infections in human oral cancers, particularly nasopharyngeal carcinomas, remain uncertain because of the limited number of investigations. This raises the question whether high-risk HPV and EBV co-infections play a significant role in the development of human nasopharyngeal carcinomas. In this paper, we propose the hypothesis that human oral normal epithelial cells, especially nasopharyngeal cells, are very susceptible to persistent HPV and EBV co-infections; therefore, high-risk HPV and EBV co-infections play an important role in the initiation of a neoplastic transformation of human oral epithelial cells. We believe that significant studies, using different cells and animal models as well as clinical samples, are necessary to answer these important questions.