PURPOSE: The combination of radiation and immunotherapy potentiated antitumor activity in preclinical models. The purpose of this study is to explore the feasibility, safety, and efficacy of a bladder-preserving approach, including dual immune checkpoint blockade and radiotherapy, in patients with muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: Patients with localized MIBC underwent transurethral resection, followed by durvalumab (1,500 mg) plus tremelimumab (75 mg) every 4 weeks for three doses and concurrent radiotherapy (64-66 Gy to bladder). Patients with residual or relapsed MIBC underwent salvage cystectomy. The primary endpoint was complete response, defined as the absence of MIBC at posttreatment biopsy. Secondary endpoints were bladder-intact disease-free survival, distant metastasis-free survival, and overall survival. RESULTS: Thirty-two patients were enrolled at six centers. Complete response was documented in 26 (81%) patients. Two patients had residual MIBC, and four patients were not evaluated. After a median follow-up of 27 months, 2 patients underwent salvage cystectomy. The 2-year rates for bladder-intact disease-free survival, distant metastasis-free survival, and overall survival were 65%, 83%, and 84%, respectively. The 2-year estimates of non-muscle-invasive bladder relapse, MIBC, and distant metastasis were 3%, 19%, and 16%, respectively. Grade 3 to 4 toxicities were reported in 31% of patients, with diarrhea (6%) and acute kidney failure (6%) being the most frequent. CONCLUSIONS: This multimodal approach including durvalumab plus tremelimumab with concurrent radiotherapy is feasible and safe, showing high efficacy in terms of response and eliciting bladder preservation in a large number of patients. Further research on this approach as an alternative to cystectomy is warranted.