Background: Patients with bulky, higher-stage small cell urothelial cancer (≥T3b, N+, and/or M+) have a high risk of developing brain metastases. Siefker-Radtke et al reported a 50% risk of brain metastases in this patient population. Therefore, a prospective trial evaluating the potential benefit of PCI was undertaken. Methods: Thirty patients with stage ≥T3b, N+, and/or M+ disease (without brain metastases on MRI) were treated between 12/2008 and 5/2018 with PCI. Patients were treated to a total dose of 30 Gy in 2 Gy fractions over 3 weeks. The patient had baseline brain MRI and mini-mental status exam (MMSE) before the treatment began. After treatment, patients underwent MRI and MMSE every 3-4 months for one year and every 6 months thereafter. If the patients did not have M+ disease at diagnosis, they were also treated with neoadjuvant chemotherapy (usually consisting of cisplatin/etoposide alternating with Adriamycin/ifosfamide), followed by a radical cystectomy. The PCI was either given between the last cycle of chemotherapy and surgery or after the surgery. Both acute and chronic toxicity from PCI were measured using CTCAE 3.0. Change in the MMSE after PCI was evaluated using a t-test. Results: Twenty-nine patients were evaluable. Twenty-four patients had ≥T3b and/or N+ disease and 5 patients had M1 disease. Median follow-up was 22 months (range 8-103 months). Four patients have developed brain metastases with a median time of 11.5 months after PCI (range 3-23 months). Two of these patients have died. Nine other patients have died from progressive systemic disease, but they did not have evidence of brain metastases. PCI was well-tolerated, with no grade ≥2 toxicity seen. Acute grade 1 toxicity seen included headache, nausea, and dermatitis. MMSE were available for 19 patients with a median follow-up of 13 months (range 3-87 months). There was no significant change in the MMSE scores after the PCI when compared to baseline (p = 0.61). Conclusions: In this study, PCI decreased the risk of developing brain metastases in patients with bulky, higher-stage small cell urothelial cancer from 50% (historical) to 13.8% without significant toxicity. Clinical trial information: NCT00756639