Background HYPO-RT-PC is a phase 3 trial comparing ultra-hypofractionated and conventionally fractionated radiotherapy in intermediate-to-high-risk localised prostate cancer. This 10-year update reports long-term efficacy and toxicity outcomes. Methods In this open-label, randomised, phase 3, non-inferiority trial done in ten centres in Sweden and two in Denmark, we recruited men aged 75 years or younger with intermediate-risk or high-risk prostate cancer and a WHO performance status between 0 and 2. Previous or current androgen deprivation therapy was not permitted. Patients were randomly assigned (1:1) to ultra-hypofractionated radiotherapy (42 & centerdot;7 Gy in seven fractions, 3 days per week for 2 & centerdot;5 weeks) or conventionally fractionated radiotherapy (78 & centerdot;0 Gy in 39 fractions, 5 days per week for 8 weeks). Randomisation was performed with a minimisation algorithm balancing T stage, Gleason score, prostate-specific antigen, and trial centre. The primary endpoint was failure-free survival, defined as time from randomisation to the first occurrence of biochemical failure, evidence of clinical progression, initiation of androgen deprivation therapy, or death from prostate cancer, analysed in the per-protocol population. The non-inferiority margin was 4% at 5 years and had previously been met, corresponding to a critical hazard ratio (HR) limit of 1 & centerdot;338. Toxicity was assessed using the Radiation Therapy Oncology Group morbidity scale. Here, we report long-term efficacy and safety results at 10 years. The trial is registered with the ISRCTN registry, ISRCTN45905321, and is closed. Findings Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionated radiotherapy (n=602) or ultra-hypofractionated radiotherapy (n=598). Ten patients withdrew consent, eight were found to be ineligible, and two died of reasons unrelated to prostate cancer. 1180 patients constituted the per-protocol population (591 in the conventional fractionation group and 589 in the ultra-hypofractionation group). After a median follow-up of 10 & centerdot;6 years (IQR 9 & centerdot;0-13 & centerdot;0) in the conventional fractionation group and 10 & centerdot;7 years (9 & centerdot;1-12 & centerdot;7) in the ultra-hypofractionation group, 205 and 178 primary events were observed, respectively. 10-year failure-free survival was 65% (95% CI 61-69) in the conventionally fractionated group and 72% (68-76) in the ultrahypofractionated group. The adjusted HR for the primary endpoint was 0 & centerdot;84 (95% CI 0 & centerdot;69-1 & centerdot;03; Cox regression analysis), confirming non-inferiority. The 10-year cumulative incidence of late grade 2 or worse genitourinary toxic effects was 30% (95% CI 26-34) in the conventional fractionation group and 28% (24-32) in the ultra-hypofractionated group (HR 1 & centerdot;01, 95% CI 0 & centerdot;81-1 & centerdot;25; p=0 & centerdot;95). For late grade 2 or worse gastrointestinal toxic effects, the corresponding figures were 14% (95% CI 11-18) and 14% (11-17; HR 0 & centerdot;94, 95% CI 0 & centerdot;70-1 & centerdot;28; p=0 & centerdot;72). Interpretation This 10-year follow-up confirms the non-inferiority of the ultra-hypofractionated radiotherapy regimen compared with the conventionally fractionated, with similar toxicity profiles. The findings support the seven-fraction schedule as a safe, effective, and practical standard-of-care option for patients with intermediate-risk prostate cancer. Funding The Nordic Cancer Union, the Swedish Cancer Society, the Swedish Research Council, the Swedish Prostate Cancer Association, and Cancerforskningsfonden i Norrland.