Patients experiencing severe side effects when taking high-risk drugs may have a significantly reduced health-related quality of life (QOL); therefore, it is important to identify changes in the health-related QOL in these patients. This study aimed to determine the health-related QOL in community pharmacy outpatients taking high-risk drugs. This prospective observational study was conducted in 29 community pharmacies with 71 pharmacists in 12 regions and cities in Japan from October to December 2020 and 760 patients were enrolled. Using descriptive questionnaires of EuroQOL-5-dimensions-5-levels (EQ-5D-5L), community pharmacists obtained health-related QOL data from outpatients taking high-risk drugs. The mean health-related QOL of all outpatients was 0.869. The health-related QOL decreased with increasing age. The outpatient health-related QOL was 0.700, 0.763, 0.785, and 0.817 when taking antiepileptic, antidepressant, digitalis, and antiarrhythmic drugs, respectively, which was lower than the average health-related QOL of all outpatients. Mobility and pain/ discomfort accounted for a large proportion of the decline in the health-related QOL with increasing age. There were no significant differences in personal care with increasing age; however, the number of outpatients with mobility, normal activity, and pain challenges decreased with age. In contrast, outpatients aged <65 years with anxiety/depression showed a lower than overall average health-related QOL. To the best of our knowledge, this is the first study in Japan to report an investigation by community pharmacists regarding health-related QOL assessment in outpatients taking high-risk drugs.