Background: Two recent large randomized trials confirm that 60Gy in 20 fractions is an effective regimen compared to conventionally fractionated escalated doses in localized prostate cancer. However, in these two trials the prostate was the only target volume irradiated. The purpose of this study is to report acute and late toxicity in patients with high-risk prostate cancer treated with the same moderate hypofractionated radiotherapy (HypoRT) to two target volumes at the same time: prostate and pelvic nodes. Methods: High-risk prostate cancer patients received 60Gy/20 fractions (4 weeks) to the prostate while the pelvic-nodes received 44Gy delivered with intensity modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) during the same 20 fractions. ADT started 2-3 months before HypoRT. Acute and late toxicity were prospectively assessed according to CTCAE.v3. Results: 105 patients treated between September/2010 and November/2013 were reviewed. Median follow up is 41 months. Median ADT duration was 18 months. Acute grade > 2 gastrointestinal (GI) or genitourinary (GU) toxicity was seen in 17% and 17% respectively, with only 1 and 3 patients experiencing GI and GU acute grade 3 toxicity, respectively. The worst grade > 2 late GI and GU toxicity was seen in 7% and 8% of patients, respectively. There was no grade 4-5 toxicity. At the last follow-up, the rates of grade = 2 GI and GU toxicity were 5% and 3%, respectively with no residual grade > 3 toxicity. The 48-month actuarial progression free survival is 82%. We found only 8 publications on this topic, all delivered the HypoRT in 25-28 fractions, but only one has long-term toxicity. Conclusions: ADT with HypoRT delivered with IMRT and SIB to the prostate (60Gy) and pelvic nodes (44Gy) in 20 fractions is feasible and well tolerated after 41months of median follow-up. Our approach shortens treatment duration, is convenient and its results support a needed randomized trial. Clinical trial information: NCT02107287