Background: This exploratory, registry-based, cross-sectional study aimed to evaluate patients' health-related quality of life (HRQOL) in a subsite of oropharyngeal cancer: cancer of the base of the tongue (CBT). Methods: CBT patients, treated with curative intent, completed the EORTC QLQ-C30 and QLQ-H&N35 questionnaires 15 months after diagnosis. The HRQOL of CBT patients was compared to reference scores from the general population and to that of tonsillar carcinoma patients. Results: The 190 CBT patients scored significantly worse than members of the general population on most scales. CBT patients with human papilloma virus (HPV)-positive tumors had significantly better HRQOL on 8 of 28 scales than HPV-negative patients. Compared to 405 tonsillar carcinoma patients, CBT patients had significantly worse HRQOL on 8 of the 28 scales, the majority local head and neck related problems. Conclusion: One year after treatment, CBT patients' HRQOL was significantly worse in many areas compared to that of the general population and slightly worse than that of tonsillar carcinoma patients. © 2021 Wiley Periodicals LLC.