Recent studies have suggested that there are benefits from the use of high-dose parenteral medroxyprogesterone acetate (MPA) in the treatment of metastatic breast cancer. The present study was designed to assess the efficacy and toxicity of high-dose oral MPA in women with clinical parameters suggesting potentially hormonally sensitive metastatic breast cancer. The first 28 patients received 800 mg/day, and 11 of them had received no previous hormone (NPH) therapy. The response rate (complete plus partial) was 63% for those receiving NPH and 12% for those receiving previous hormone (PH) therapy. Toxicity was significant at these doses, especially for women treated for more than 5 weeks. Toxic effects included excessive weight gain, Cushingoid facies, worsening of diabetes mellitus, and other stigmata suggestive of hypercorticism. Nineteen other patients were treated at 400 mg/day with a 60% response rate for 10 NPH patients and 44% for patients with PH treatment. Toxicity was less severe in these patients. The median time to treatment failure was 23 weeks, and to survival, 119 weeks for all treated patients. Moderately high (400 mg/d) and higher dose (800 mg/d) oral MPA are capable of inducing reasonable response rates in patients with NPH treatment. The toxicity of these regimens was significant--profound weight gain was dose limiting in some patients. While effective, high-dose oral MPA is unlikely to supplant tamoxifen as first-line therapy in metastatic breast cancer.