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 <0.001). Meanwhile, a good agreement was revealed between HPV16 DNA and p16 IHC results (κ = 0.608, P-value <0.001). Similarly, there was a good agreement between HPV RNA results and p16 IHC results (κ = 0.608, P-value <0.001). By the end of the study period, 13.7% of the enrolled patients died, with the overall survival of the studied patients being 17.29 months. Of note, there was no statistically significant correlation between the overall survival and HPV status. Conclusion: The present study highlights the significant role played by HPV in HNSCC. Furthermore, it reveals that although p16 has been a marker of HPV existence in HNSCC, it should not be the sole determinant of HPV role in tumorigenesis.