This study investigates the prognostic significance of human papillomavirus (HPV) status in oropharyngeal squamous-cell carcinoma. The analysis is based on a retrospective review of patients enrolled in a randomized clinical trial comparing accelerated-fractionation radiotherapy with standard-fractionation radiotherapy, both combined with cisplatin therapy. The median follow-up period was 4.8 years. The 3-year overall survival rate was similar between the two treatment groups (70.3% vs. 64.3%). However, patients with HPV-positive tumors had significantly better overall survival (82.4% vs. 57.1%) and progression-free survival (73.7% vs. 43.4%) compared to those with HPV-negative tumors. Multivariable analysis showed that HPV status, tobacco smoking, age, race, performance status, tumor stage, and nodal stage were significant determinants of survival. Recursive-partitioning analysis classified patients into low, intermediate, and high risk based on these factors. HPV-positive tumors were associated with lower risk, while tobacco smoking was associated with higher risk. The study concludes that tumor HPV status is a strong and independent prognostic factor for survival in oropharyngeal squamous-cell carcinoma, suggesting that future clinical trials should be designed to stratify patients based on HPV status.This study investigates the prognostic significance of human papillomavirus (HPV) status in oropharyngeal squamous-cell carcinoma. The analysis is based on a retrospective review of patients enrolled in a randomized clinical trial comparing accelerated-fractionation radiotherapy with standard-fractionation radiotherapy, both combined with cisplatin therapy. The median follow-up period was 4.8 years. The 3-year overall survival rate was similar between the two treatment groups (70.3% vs. 64.3%). However, patients with HPV-positive tumors had significantly better overall survival (82.4% vs. 57.1%) and progression-free survival (73.7% vs. 43.4%) compared to those with HPV-negative tumors. Multivariable analysis showed that HPV status, tobacco smoking, age, race, performance status, tumor stage, and nodal stage were significant determinants of survival. Recursive-partitioning analysis classified patients into low, intermediate, and high risk based on these factors. HPV-positive tumors were associated with lower risk, while tobacco smoking was associated with higher risk. The study concludes that tumor HPV status is a strong and independent prognostic factor for survival in oropharyngeal squamous-cell carcinoma, suggesting that future clinical trials should be designed to stratify patients based on HPV status.