Abstract Treatment with the progesterone receptor modulator, mifepristone, has provided patients with advanced adenocarcinomas, even those devoid of the classic nuclear progesterone (P) receptor, who had previously progressed off of standard chemotherapy, immunotherapy, or targeted therapy, significant palliative benefits and extension of life. The purpose of this research was to determine if mifepristone could similarly provide benefits for a sarcoma, namely, a metastatic fibroblastic osteosarcoma, that had progressed despite treatment with surgery, radiation, and chemotherapy. A 51 year old male was diagnosed at age 46, with an osteosarcoma of the right leg. He had neoadjuvant radiation therapy and a resection of the right proximal tibia to remove a 6cm tumor. This was followed by a chemotherapy cocktail of doxorubicin, cisplatin and high dosages of methotrexate for 9 months. Unfortunately, a tumor recurred and it was again resected. Since he was also found to have a 1.6 × 1.3cm upper lung nodule and another right lower lung nodule, he was also treated with ifosamide and etoposide for 5 months. Subsequently, these 2 drugs were continued for another 6 months alternating with high dose methotrexate. Foundation one testing revealed targeted mutations for CD104, FGRI, and KRAS, leading to treatment with a targeted therapy, regorafenib. However, 8 months later imaging studies showed progression of disease. Mifepristone, 200mg orally, was then added. CT scans had shown a steady decline in his condition until mifepristone was started. After 3 months of therapy, he showed stable disease with no increase in size of his metastatic lesions, or any new ones. He feels better on mifepristone than he has felt on any of his previous therapies, even when his disease was not as advanced. He has now completed five months of the combination therapy. He has neuropathies, manifested as pain in his hands and feet and somnolence from the regorafenib and no new side effects from mifepristone. This is the first non-gynecologic sarcoma, not known to be associated with the presence of the nuclear P receptor, reported to respond to mifepristone. There had been a previous case of widely metastatic leiomyosarcoma that showed dramatic response to mifepristone. The hypothesized mechanism of action for mifepristone in inhibiting growth and spread of metastatic cancer, is by inhibiting the production of the immunomodulatory protein the progesterone induced blocking factor (PIBF), actually secreted by the cancer cells themselves into the tumor microenvironment that results from activation of membrane P receptors. PIBF protein suppresses the cellular immune reaction to the tumor cells. Mifepristone, by blocking this membrane P receptor, inhibits PIBF production. Fibroblastic osteosarcoma can be added to the long list of advanced cancers, resistant to standard cancer therapy, yet demonstrating palliative benefits from mifepristone treatment. Citation Format: Jerome H. Check, Diane Check, Trina Poretta, James Aikins, Carrie Wilson. Palliative benefits of oral mifepristone treatment for metastatic fibroblastic osteosarcoma [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 696.