Background: The place of short term androgen deprivation therapy (STADT) in combination with radiotherapy (RT) for patients with intermediate risk prostate cancer (IRPC) remains controversial. The purpose of this prospective, randomized trial was to compare outcomes between patients with IRPC treated with different doses of RT with or without STADT, (PCS III trial, Clinical Trials.gov, #NCT00223145). Methods: From December 2000 to September 2010, 600 patients with IRPC were randomized to 6 months of STADT and two levels of prostate RT doses of 70 (arm 1) or 76 Gy (arm 2) versus prostate dose-escalated RT alone at 76 Gy (arm 3). STADT consisted of bicalutamide and gosereline for six months. RT (2 Gy per fraction) started four months after the beginning of STADT. Biochemical failure and disease-free survival (DFS) were primary end-points, with overall survival (OS) as secondary endpoint. DFS and OS rates were estimated with Kaplan-Meier and compared with log rank test and Cox regression. Results: Patient’s characteristics were well balanced among the 3 arms (median age 71 years, median PSA 10 ng/ml, median Gleason score 7 and clinical stage). At a median follow-up of 6.5 years, biochemical failure occurred in 96 (16%) patients (arms 1 to 3: 13.5%, 11%, 23.5%) with statistical difference between arm 1 and 3 (p = 0.01) and arm 2 and 3 (p < 0.001) but not between arm 1 and 2. A total of 130 (21.7%) patients died with only 7 deaths (1.2%) attributed to prostate cancer. The 5-/10-year DFS rates were 92.8%, 97.1% and 85.5%, and 78.4%, 78.3% and 65.9%, respectively. Significant differences in DFS between the treatment arms were observed at 5 and 10 years between arm 1 and 3 (p = 0.015, p = 0.012) and arm 2 and 3 (p < 0.001 at 5-/10-year) but not between arm 1 and 2 (p = 0.052, p = 0.385). The 5-/10-year OS rates were 90.9%, 93.6% and 90.8%, and 63.8%, 70.8% and 75%, respectively. There was no statistical difference in OS between arms at 5 and 10 years. Conclusions: In patients with IRPC, the use of STADT in association with RT, even at lower doses, leads to a superior biochemical control and DFS as compared to dose-escalated RT alone. These outcomes did not translate into an improved OS. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: #NCT00223145.