Eighty-five menopausal women (mean age 56 years) with endometrial hyperplasia without (65 patients, group 1) and with cytologic atypia (20 patients, group 2) were followed up prospectively from 2 to 12 years (mean 7 years) to shed insight into their respective response to oral medroxyprogesterone acetate therapy. In group 1 9 of 65 patients (14%) had persistence, 4 (6%) had recurrence, and none developed carcinoma. In group 2 10 of 20 patients (50%) had persistence and 5 had recurrence with cytologically atypical disease. Five of 20 patients (25%) developed adenocarcinoma at 2 to 7 years (mean 5.5 years) after starting medroxyprogesterone acetate therapy. The data suggest that most women with hyperplasia respond to progestogenic therapy and are not at increased risk of developing cancer. The patients with an unfavorable response to medroxyprogesterone acetate and a significant elevation in cancer risk can be identified on the basis of cytologic atypia.