Context and objective: Human papillomavirus (HPV) is one of the factors involved in the occurrence of head and neck squamous cell carcinoma (HNSCC). This is also considered a predictive factor for the survival of HNSCC, especially in oropharynx. The objective was to identify predictors of HNSCC-related mortality and assess the impact of HPV status on the survival of patients with HNSCC. Methods: A historical cohort study was conducted in two reference hospitals in Kinshasa between 2012 and 2023. Kaplan Meier curves were constructed to describe survival (time to death) and were evaluated using the Log-Rank test. Predictors of mortality were tested by Cox proportional hazard. Results: 95 patients (mean age 52.5 ± 15.0 years, male, 64.2%) were included. HPV-positive patients had better overall survival than HPV-negative patients (440 vs 245 days; p ≤0.001). Oropharyngeal location [HR 0.523; 95% CI 0.337 - 0.813; p=0.004] and the expression of Protein 16 (p16) [HR 0.365; 95% CI 0.221 - 0.604; p<0.001] were the predictors of mortality in bivariate analysis. After adjusting the parameters, only the expression of p16 [HR 0.334; 0.185 - 0.605; p<0.001] significantly reduced patient mortality (p<0.001). Conclusion: Positive HPV status has a significant and favorable impact on the overall survival of HNSCC patients.