Aim: To evaluate the tolerance and the clinical efficacy of hypofractionated radiotherapy in patients affected by intermediate risk prostate cancer. Patients and Methods: Between March 2007 and November 2011, 106 patients with intermediate risk prostate cancer were treated with 3-dimension conformal hypofractionated radiotherapy. Intermediate risk was defined as clinical stage T1-T2 and pre-radiotherapy PSA between 10 and 20 ng/mL, and Gleason Score equal to <7 or clinical stage T1-T2 and pre-radiotherapy PSA between less than or equal to 20 ng/mL, and Gleason Score equal to 7. Prostate biopsy was performed to all patients to confirm the diagnosis. A total dose of 43.8 Gy was delivered to seminal vesicles and 54.75 Gy to the prostate, 3.65 Gy per fraction, three times a week for a total of 5 weeks. All patients underwent neoadjuvant, concomitant and adjuvant hormonal therapy (OT) for a total duration of 9 months. Acute and late toxicities were evaluated according to RTOG scale. The nadir PSA after radiotherapy plus 2 ng/mL was used for defining biochemical relapse (Phoenix criteria). Results: Median follow-up was 25 months (range 4-55 months). Five patients (4.7%) developed biochemical failure: of these patients were found to have metastasis to regional lymphnode, while two patients developed bone metastasis. Six patients (5.9%) died from causes different from prostate cancer without biochemical failure, while patients died due to disease progression. Acute toxicities (within 3 months from the end of RT) were as follow: Grade 1 Genitourinary (GU) toxicities were 43.2%, while 10% presented Grade 2 toxicities; Grade 1 Gastrointestinal (GI) toxicities were 9.6%, Grade 2 GI toxicities were 10.8%. Late GU and GI toxicities greater than or equal to Grade 2 recorded at the last follow-up were 3.3% and 4.6% respectively. No patient developed grade 4 toxicity. 2-year BFS and 4-year BFS were 94.4% and 92%, respectively. Conclusion: The hypofractionated schedule used was well tolerated with a low rate of acute and late grade greater than or equal to 2 gastrointestinal and genitourinary toxicities. Hypofractionation is useful to obtain high rate of tumor control also if longer follow-up is needed.