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The present multi-institutional retrospective study describes the tolerance of orthotopic neobladders to moderate doses of pelvic radiotherapy in 25 patients. In the setting of high-risk muscle-invasive bladder cancer, adjuvant radiotherapy is currently under investigation in multiple international clinical trials. To the best of our knowledge, the present study is the first to report that orthotopic neobladders can tolerate moderate doses of pelvic radiotherapy without significant toxicity.The present retrospective study analyzed the tolerance of orthotopic ileal neobladders to radiotherapy by reviewing the acute and late toxicity in patients who underwent postoperative radiotherapy after radical cystectomy/cystoprostatectomy.A multi-institutional database was created for patients who had undergone radical cystectomy/cystoprostatectomy and neobladder reconstruction, followed by adjuvant radiotherapy (RT). The patient and tumor characteristics were recorded. The RT data were reviewed to determine the treatment technique used, the radiation dose received by the neobladder, and acute and late toxicity evaluated using the Common Terminology Criteria for Adverse Events, version 4.0, scale.A total of 25 patients were included, with a median age of 64 years. Of the 25 patients, 18 received a dose of 45 to 50.4 Gy. The most common reasons for postoperative radiotherapy were close or positive surgical margins and pT3-pT4 or N+ disease. Ten patients underwent intensity modulated RT. All but 1 patient completed the RT course. Of the patients who completed their RT schedule, none had grade ≥ 3 acute gastrointestinal toxicity. One patient who received concurrent chemotherapy developed grade 3 acute genitourinary toxicity. Three patients reported late grade 1 genitourinary toxicity (frequency of urination, mild leakage at night), with no reports of chronic gastrointestinal toxicity. None of the patients experienced neobladder perforation, leak, or fistula.The use of moderate doses of pelvic RT (range, 45-50.4 Gy) was well tolerated among the 25 patients who underwent RT after cystoprostatectomy with orthotopic neobladder creation. This finding supports the use of postoperative RT to moderate doses in this patient population when clinically indicated.