Background: The molecular class of endometrial cancer (EC) is both prognostic and predictive in high-risk EC (HREC). The TransPORTEC research consortium showed that patients with MMRd HREC did not benefit from adjuvant chemotherapy added to radiotherapy. MMRd tumors are particularly sensitive to immunotherapy. We hypothesize that adjuvant durvalumab added to standard radiotherapy will increase recurrence-free survival (RFS) in patients with MMRd HREC. Methods: MMRd-GREEN is an international, open-label, randomized phase III trial and part of the RAINBO program (NCT05255653). Eligible patients will be allocated (1:1) to adjuvant durvalumab 1500 mg once every 4 weeks for 1 year combined with radiotherapy or standard radiotherapy alone. The primary endpoint is RFS at 3 years. Secondary endpoints are pelvic, vaginal and distant RFS, EC-specific survival, overall survival, treatment-related toxicity, health-related quality of life and exploratory translational research. Main inclusion criteria include histologically confirmed stage IB/II with (substantial) lymph-vascular space invasion (LVSI) or stage IIIA-C MMRd EC, after hysterectomy and bilateral salpingo-oophorectomy (regardless of lymphadenectomy or sentinel lymph node biopsy) without macroscopic residual disease. Molecular classification must be performed according to the WHO 2020 algorithm. The target accrual is 316 patients, accounting for a total drop-out rate of 12%. This sample size yields 80% power to detect a 13% increase in the 3-year RFS (hazard ratio 0.58) as a result of the addition of durvalumab, with an accrual duration of 48 months and follow-up period of 30 months. No interim analysis is planned; an independent data monitoring committee will routinely monitor recurrences and adverse events. Enrollment: Since August 2022, the trial is open for recruitment in the Netherlands and per February 10^th 2023, the first 3 patients have been enrolled. Activation of more international centers is ongoing. Clinical trial information: NCT05255653.