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Radiation therapy is the most effective cytotoxic cancer therapy available for the treatment of localized tumors. However, radiation-induced toxicity to normal tissues limits the radiation dose and therefore the curative potential of radiotherapy. In particular, the highly radiosensitive intestine greatly limits the use of radiation for patients with intra-abdominal tumor diseases including women with ovarian cancer. Here we sought to investigate the safety and efficacy of FLASH radiation therapy in the treatment of widespread ovarian cancer peritoneal metastases. We performed abdominal irradiation on healthy and ovarian tumor-bearing mice at conventional (CONV, (0.07 Gy/sec)) or FLASH (200 Gy/sec) dose rates and examined gut function by stool counts, DNA damage in crypt cells by γ-H2AX staining, cell death and proliferation by TUNEL/ caspase-3 staining and BrdU immunohistochemistry respectively. We report that ultrahigh dose rate FLASH irradiation causes significantly less radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to CONV dose rate irradiation. Abdominal FLASH reduced the mortality from gastrointestinal syndrome, preserved gut function and epithelial integrity as reflected by their stool counts and FITC-Dextran analysis. In addition, we found decreased cell death and enhanced proliferation of crypt base columnar cells (CBCs) following FLASH irradiation in comparison to CONV irradiation. We also detected reduced number of γ-H2AX foci in crypt cells indicating less DNA damage and/or increased DNA repair after FLASH compared to CONV irradiation. Importantly, FLASH and CONV irradiation have similar efficacy in the reduction of ovarian cancer peritoneal metastases. These findings suggest that FLASH irradiation has biological advantages compared to conventional dose rate irradiation in reducing radiation-induced intestinal injury within the irradiation field and therefore may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of abdominal and pelvic tumor disease. Citation Format: Suchitra Natarajan, Karen Levy, Jinghui Wang, Stephanie Chow, Joshua Eggold, Phoebe Loo, Rakesh Manjappa, Frederick M. Lartey, Emil Schüler, Lawrie Skinner, Marjan Rafat, Ryan Ko, Anna Kim, Duaa Al Rawi, Rie von Eyben, Oliver Dorigo, Kerriann M. Casey, Edward E. Graves, Karl Bush, Amy S. Yu, Albert C. Koong, Peter G. Maxim, Billy W. Loo, Erinn B. Rankin. FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5351.