Introduction: Human papillomavirus (HPV) is identified as a culprit in a subset of head and neck squamous cell carcinomas (HNSCCs). The clinicopathologic profile displayed by this subset diverges from that of HPV-negative HNSCCs. Despite a variety of available tests, there is no consensus on which technique is the best for detection of HPV in HNSCCs. Although this field has received substantial interest within different continents, African and Egyptian populations are not yet well studied within the literature. Methods: This cross-sectional study was carried out to detect HPV prevalence in HNSSC and to correlate the viral prevalence with different clinicopathologic parameters as well as with the patients’ outcome. For 51 patients with HNSCC, HPV-16 DNA was determined via PCR, while E6/ E7 mRNA was detected employing real-time PCR. Immunohistochemistry (IHC) was performed to assess p16 status. Results: P16 was overexpressed in 49% of cases, while HPV-16 DNA was detected in 52.9% of cases, and likewise, E6/E7 mRNA was found in 52.9% of cases. There was a very good agreement between HPV16 DNA and RNA results (κ = 0.843, P-value