Abstract Background: For patients with castration-resistant prostate cancer (CRPC) metastatic to bone, treatment with bone seeking radiopharmaceuticals is an important treatment option, both for pain palliation and improvement of survival. Radium-223-chloride (an alpha-emitter) has a proven survival benefit. Some small clinical studies suggest that rhenium-188-HEDP, a beta-emitter that is well-known for its effect on pain palliation, may have a beneficial effect on survival as well. A major advantage of rhenium-188-HEDP, compared to radium-223-chloride is the production on-site at a healthcare institute, resulting in rapidly availability and lower costs. Other advantages of rhenium-188-HEDP includes more favorable physical characteristics (shorter half-life and longer penetration depth) and being more patient-friendly (3 instead of 6 administrations) compared to radium-223-chloride. Despite some promising data in small randomized studies, the potential effect on patient survival of rhenium-188-HEDP needs to be established in a randomized phase III study. Methods: The RaRe trial is a multicenter, randomized, open-label, controlled phase III study comparing the efficacy of repeated treatment with radium-223-chloride and repeated treatment with rhenium-188-HEDP in patients with CRPC metastatic to bone. The aim of the trial is to include 402 participants who are randomized to one of the two treatment groups in a 1:1 ratio. The primary endpoint is overall survival (OS), and the secondary endpoints are pain response, quality of life (QoL), time to first occurrence of skeletal related event (SRE), prostate specific antigen (PSA) progression, total alkaline phosphatase (tALP) progression, and incremental cost-effectiveness. An interim analysis for futility will be performed after the inclusion of 90 patients in each treatment group. Discussion: In this randomized phase III trial we hypothesize that treatment with rhenium-188-HEDP results in an improved survival in patients with CRPC metastatic to bone as compared to the current standard treatment with radium-223-chloride. We also expect to demonstrate that treatment with rhenium-188-HEDP improves pain response and quality of life of CRPC patients. Results coming from this study may help to find a better treatment for CRPC patients, while reducing costs. In current times of exponential growth of healthcare costs, we believe that this study is meaningful from the perspective of cost-effectiveness. Clinicaltrials.gov identifier: NCT03458559. Registered 8 March 2018. Trial status: recruiting. Citation Format: Jessica C. Notohardjo, Esther W. Bouman-Wammes, Joyce M. van Dodewaard - de Jong, Haiko J. Bloemendal, Rogier Lange, Rob ter Heine, Henk M. Verheul, John M. de Klerk, Alfons J. van den Eertwegh. Repeated radium-223-chloride versus rhenium-188-HEDP in patients with metastatic castration-resistant prostate cancer: RaRe study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT145.