PURPOSE: A novel classification system has been proposed to stratify patients undergoing palliative radiation therapy based on their pain response and time to progression. This study used prospective observational data to quantify quality of life (QoL) changes associated with pain response and the classification system. METHODS AND MATERIALS: Between August 2021 and September 2022, 366 painful lesions with a numerical rating scale of 2 or more from the 261 eligible patients underwent palliative radiation therapy. Patients were followed-up prospectively at 2, 4, 12, 24, 36, and 52 weeks postradiation therapy, with EORTC QLQ-C15-PAL and QLQ-BM22 questionnaires obtained simultaneously with pain response assessments. The primary endpoint was defined as the global health status/QoL improvements at 12 weeks based on minimally clinically important differences and compared by the pain response (responders vs. nonresponders) and by class 1 (no opioids, no reirradiation, n = 89), 2 (neither class 1 nor 3, n = 211), and 3 (opioids and reirradiation, n = 66). RESULTS: With a median follow-up time of 21 weeks for pain response and 13 weeks for QoL assessment, 1773 pairs of QLQ-C15-PAL and QLQ-BM22 questionnaires were collected. The QoL assessment at baseline was covered with 97% (355/366) of lesions and 67% (183/273) at 12 weeks: this compliance was lower in nonresponders than in responders (57% vs. 72%, P = .004) and highest in class 1, followed by classes 2 and 3 (70% vs. 44% vs. 39%, P = .001). The improvement rate was significantly different by class, with class 3 having the lowest in all subscales except nausea and psychosocial aspects: the improvement rate of global health status/QoL was 33% in class 1, 31% in class 2, and 20% in class 3, P = .001). CONCLUSIONS: The QoL changes associated with pain response and the classification system were identified, suggesting that the classification system may help identify populations more or less likely to improve QoL, in addition to separating pain response rates.