Head and neck squamous cell carcinomas (HNSCCs) remain a significant cause of morbidity and represent the sixth most common malignancy diagnosed worldwide. Tobacco use and alcohol consumption are the most important risk factors for the development of HNSCC. However, epidemiological studies reported an association with human papillomavirus (HPV) infection in a subgroup of HNSCCs. The prognosis of patients with HPV-positive HNSCC is widely discussed in the literature, with contradictory results being reported. Most authors report that the presence of HPV is a favorable prognosis factor with regard to recurrence and survival. However, other studies did not show a correlation between HPV infection and clinical outcomes or showed that HPV-positive patients had a worse prognosis. In this review, we propose various hypotheses that could explain this discrepancy including the anatomical site, patient immunosuppression caused by the virus or cigarette smoking and the interactions between tobacco and HPV. In fact, smoking and immunosuppressive status could have the potential to favor the carcinogenic effect of HPV. We also suggest that it is important to separate clearly HPV-positive HNSCC tumors related to tobacco and alcohol consumption from HPV-positive HNSCC tumors without these classical risk factors in order to evaluate the prognosis.