OBJECTIVE Mifepristone (RU486) is a progesterone receptor (PgR) antagonist that has been shown to be active in some preclinical hormone-dependent breast cancer tumor models and to produce a few responses in patients with pretreated metastatic disease in two small trials. This trial was designed to assess the response rate and toxic effects of mifepristone in a favorable group of women with PgR-positive recurrent breast cancer who had received no prior therapy. METHODS Postmenopausal patients with PgR-positive, bidimensionally measurable disease were eligible provided they had received no other therapy for recurrence. Prior adjuvant hormonal treatment was permitted if a disease-free interval of at least 24 months had been observed. Mifepristone 200 mg was given daily and disease was reassessed every 4 weeks. Standard criteria for tumor response and toxic effects were used. RESULTS A total of 28 patients were registered in the trial: all were eligible and assessable. Three partial responses were noted for an overall response rate of 10.7% (95% confidence interval [CI], 2% to 28%). Toxic effects were generally mild to moderate and consisted primarily of nausea, lethargy, anorexia, and hot flashes. CONCLUSIONS Mifepristone had minimal activity in this optimal group of patients. While there may be reason to conduct some clinical studies with it in combination with antiestrogens on the basis of some preclinical work, our data do not support its use as a single agent in the management of breast cancer.