Background: Combined-modality treatments are bladder-preserving alternatives for patients (pts) who are not candidates for radical cystectomy by medical reasons, refusal, or patient´s choice. Immune therapies seem to potentiate tumor-specific immune response induced by radiotherapy (RT). Combination of RT with anti-PD-1/PD-L1 therapy appears safe and there are signs of promising activity. The aim of this study is to assess the efficacy and safety of atezolizumab (ATZ) concurrent with external beam radiotherapy (EBRT) for the treatment of muscle-invasive bladder cancer (MIBC) with bladder preservation intent. Here we present an interim analysis. Methods: This is an open, multicenter, and phase II trial, sponsored by SOGUG, in pts with confirmed diagnosis of MIBC in clinical stages cT2-T4a N0 M0 who are not candidates for radical cystectomy. Treatment consists of 6 doses of ATZ 1200 mg IV every 3 weeks, starting on day 1 of EBRT, and 60 Gy of RT in 30 fractions over 6 weeks at 2 Gy/day. The primary endpoint of the study is pathological complete response (pCR) defined as a response of grade 5 according to Miller and Payne criteria, 1 to 2 months after the last dose of ATZ. A planned interim analysis has been performed (data cut-off date: November 2021) on the primary endpoint to avoid exposure to ineffective treatment according to the minimax two-stages Simon’s design (stopping rule: 9 out of the first 13 evaluable pts should achieve pCR). Incidence of adverse events (AE) and serious AE (SAE) has been also secondarily assessed. Results: From September 2019 to November 2021, 39 pts were screened, of whom 13 were excluded due to non-compliance with eligibility criteria. Thus, the evaluable population consisted of 26 pts. The safety analysis was performed in 22 pts who had received at least one dose of ATZ. 14 pts were assessed pathologically and, thus, included in interim efficacy analysis (median age: 78.6 years; clinical stage: 71.4% T2a, 14.3% T2b, 7.1% T3a, 7.1% T3b). All 14 pts had achieved pCR at the cut-off date. 20/22 (91%) pts experienced at least one AE, with asthenia (11 pts), diarrhea (9 pts), and urinary tract infection (4 pts) being the most common. 9 SAEs were reported in 7 (32%) pts (bacteriemia, COVID-19 infection, depressed LVEF, unknown origin fever, hepatic toxicity, kidney failure, rectorrhagia, respiratory infection, and urinary sepsis). 6 (27%) pts suffered AEs leading to treatment discontinuation. No AEs leading to death occurred. 17 pts with available data on survival were alive at the cut-off date. Conclusions: Interim results suggest that ATZ combined with EBRT is a feasible and effective treatment in terms of pCR, with a manageable safety profile. The final results from this trial will provide information about its effects on clinical outcome, including survival and updated safety findings. Clinical trial information: NCT04186013.