Background: Dose-escalated prostate radiotherapy (PRT) with androgen deprivation therapy (ADT) is a standard curative treatment for localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. We report the patient-reported health related quality of life (HR-QoL) outcomes from a phase III study exploring optimal sequencing of PRT with ADT in LPCa. Methods: Newly diagnosed LPCa patients with Gleason score ≤7, clinical stage T1b-T3a, and PSA < 30 ng/mL were randomized to receive PRT (76 Gy/38 fractions) with 6 months (mos) of ADT starting 4 mos prior to RT (NAHT arm) or concurrently with RT (CAHT arm). HR-QoL was assessed using EORTC QLQ-C30 and PR25 at baseline, q2 mos while on ADT, q4 mos for year 1 and 2 after ADT, q6 mos from year 3 to 5 and annually thereafter. Linear mixed modelling was applied to compare change in score (relative to baseline) over time. Wilcoxon rank-sum test was used to identify between-group difference in absolute scores, at 18, 36 and 60 mos. The statistical and clinical significance was set at p≤0.01 and 10-point threshold, respectively. Results: Overall 432 men were enrolled in the study and 393 (194 in NAHT and 199 in CAHT arm) were eligible for HR-QoL evaluation. There was a significant difference in the change in score of sleep disturbance due to urinary bother (least-squared mean: 3.9 vs. 7.6, P = 0.001) between the two arms. Although there were statistically significant differences in absolute scores of global QoL (18, 60 mos), cognitive (18, 60 mos), social and emotional functions (60 mo), sexual intimacy (18 mo) and fatigue (60 mo) favoring NAHT, the only clinically meaningful difference was noted in ejaculatory dysfunction at 18 (mean: 52.5 vs. 64.6), 36 (60.2 vs. 49.2) & 60 mos (61.4 vs. 50.9), respectively. Conclusions: We did not find any notable difference between the two arms with respect to score change over time in any of the HR-QoL metrics except sleep disturbance due to urinary bother. Clinically meaningful difference was noted only in the late absolute ejaculatory dysfunction score which favored the NAHT arm. Based on these findings, both NAHT and CAHT with PRT are reasonable standards of care for LPCa. Clinical trial information: DC-990-0082.