Background: Acute and late radiation cystitis is a common adverse effect of cancer treatment with radiotherapy to the pelvic area. We hypothesised that hyaluronic acid and chondroitin sulphate may provide protection of the urothelium during radiotherapy and alleviate acute and chronic consequences of pelvic radiotherapy. Methods: This randomised, controlled, multicentre study was done across seven centres in four countries. Male patients aged ≥18 years scheduled to undergo primary intensity‐modulated radiotherapy for localised prostate cancer were enrolled. Patients were randomised to intravesical hyaluronic acid plus chondroitin sulphate plus an oral soft gel formulation of curcumin, quercetin, hyaluronic acid, and chondroitin sulphate. No masking was applied. The primary endpoint were absolute change from baseline to follow-ups in the urinary domain score of the Expanded Prostate Cancer Index Composite (EPIC), the ICIQ-Male Lower Urinary Tract Symptoms (ICIQ-MLUTS) questionnaire, and the EuroQol Group questionnaire EQ-5D-5L. Secondary outcomes was the rate of patients who stopped treatment due to intolerance or adverse events. Findings: Of 57 patients screened between January 2017 and May 2019, 49 were enrolled and randomly assigned to either active (intravesical plus oral, n=25) treatment or controls (no treatment, n=24). Three patients in the control group withdrew after randomisation. When stratified according to urinary symptoms and impact of symptoms on quality of life, sub-total scores and total score were lower from baseline to 12 months in controls (p=0.05, p=0.003, and p=0.008, respectively). There was a significant time*group interaction in favour of active treatment for incontinence symptom score (p=0.011) and bother score (p=0.017). Interpretation: Our results suggest that intravesical hyaluronic acid plus chondroitin sulphate in combination with a hyaluronic acid and chondroitin-containing oral formulation are a safe and well tolerated treatment to reduce the acute and chronic urinary adverse consequences of pelvic radiotherapy. Trial Registration: The study was registered with ClinicalTrials.gov (NCT03493997). Funding Statement: (TETI Association) IBSA SA supplied freely Ialuril and Ialuril Soft Gels Declaration of Interests: All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the responsible institutions for medical research ethics for all participating centres and was conducted in compliance with the International Conference on Harmonization/Good Clinical Practice guidelines, national laws, applicable regulatory requirements, and the ethical principles of the Declaration of Helsinki. Specifically, the study was approved by the Ethics Committees of the Universidad Autonoma de Barcelona, Barcelona, Spain, the Universita Vita-Salute San Raffaele, Milan, Italy, the Ospedali Careggi, Firenze, Italy, the University of Palermo, Italy, the St. Cyril and Method University Hospital Bratislava, Slovakia, the Fakultna nemocnica s poliklinikou Presov, Slovakia, and Istanbul University, Istanbul, Turkey.