Post-prostatectomy radiotherapy (RT) is a common second-line treatment for patients with prostate cancer. In the phase III randomized NRG-GU003 trial, hypofractionated postprostatectomy RT (HYPORT) was compared with conventionally fractionated postprostatectomy RT (COPORT) in terms of patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms in patients with prostate cancer who had received prostatectomy. Overall, 296 patients were randomized to receive HYPORT (144) or COPORT (152). No differences in the patient-reported GU symptoms were observed after RT in the HYPORT versus the COPORT group, and these results were maintained at 6 and 12 months post-RT. Patient-reported GI symptoms were greater in patients receiving HYPORT than patients in the COPORT group at the end of the RT treatment, but this difference was abolished within 6 months. At the median follow-up time of 2.1 years, no differences in GI and GU symptoms were reported between the two groups of patients. These results indicate that HYPORT can be a new acceptable practice standard for patients with prostate cancer after prostatectomy, with the benefit of reducing time commitment and treatment-associated expenses, potentially increasing access to therapy.