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To report a finding of persistently elevated estradiol (E2) after prolonged mifepristone use for treatment of progesterone-receptor positive meningioma, an association which has not previously been reported.This is a case report.Outpatient Reproductive Endocrine clinic at a tertiary referral center.A 48-year-old gravida 1 para 0-0-1-0 with progesterone-receptor positive meningioma, recurrent after multiple debulking surgeries. Patient was treated with mifepristone for 11 years with symptomatic improvement and tumor shrinkage. Levels of follicle-stimulating hormone, luteinizing hormone, and estradiol (E2) were followed throughout the patient’s course of mifepristone therapy. E2 levels were found to be persistently elevated to 500–700 pg/mL.Enhanced E2 assay, a liquid-chromatography tandem mass spectrometry (LC-MS/MS) based assay, was measured simultaneously with the routinely used immunoassay for 5 years in attempt to obtain a more accurate assessment.E2 levels using the standard immunoassay were found to be persistently elevated while the patient was taking mifepristone. Using the enhanced LC-MS/MS assay, E2 was initially elevated, however was subsequently low. After the patient discontinued the medication, E2 levels as measured by the immunoassay normalized.Prolonged mifepristone use was found to be associated with markedly elevated E2 levels in our patient. If this is a true elevation, it may help explain the incidence of endometrial hyperplasia and endometrial polyps with prolonged mifepristone use. However, this was likely a false elevation, potentially due to cross-reactivity of mifepristone with the immunoassay, given the normal values obtained with the enhanced LC-MS/MS E2 assay. Whether prolonged mifepristone use may cause true or falsely elevated E2 in a wider population, and the mechanism through which it does so, should be further investigated.