The present study evaluates clinical outcomes and treatment-related toxicity following definitive ultra-high single dose external beam radiotherapy delivered to patients with low- or intermediate-risk adenocarcinoma of the prostate. Modern computer-driven technology enables the implementation of ultra-high Single-Dose Image-Guided Radiotherapy (SD-IGRT) safely. Prostate cancer patients classified according to the current National Comprehensive Cancer Network (NCCN) guidelines as low or intermediate risk (biopsy Gleason score of ≤7 and/or Prostate Specific Antigen (PSA) level ≤20 ng/mL and/or Stage T1, T2a, T2b or T2c) are eligible for this study. Patients will undergo SD-IGRT with volumetric intensity-modulated arc radiotherapy (VMAT) with state-of-the-art treatment-planning and quality assurance procedures. Emphasis is placed on normal tissue sparing and delivery accuracy via the use of devices that ensure stability and beam location reproducibility. A rectal balloon with air filling will be used for prostate target immobilization and anatomical reproducibility, while a urethral catheter loaded with beacon transponders will be used to ensure set-up reproducibility and online target tracking. Previously untreated patients with low- or intermediate-risk prostate cancer will receive 24 Gy in a single-dose. Patients will be followed at one month post-treatment and every 3 months for up to 12 months (+/- 4 weeks) and every 6 months thereafter. Acute and chronic toxicity evaluations will focus, though not exclusively, on urinary, rectal and sexual functions and will be assessed through validated EPIC questionnaires. Serum PSA values will be drawn on the same schedule as clinical follow-up. A multi-parametric MRI will be performed at baseline, and at 6, 12 and 24 months following intervention. The study will be continuously monitored for a minimum of 5 years.