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Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC.This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20–40 years). MPA (400 mg/day) and metformin (750–2250 mg/day) were administered for 24–36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set.The body mass index was ≥25 kg/m2 in 27 patients (mean, 31 kg/m2; range, 19–51 kg/m2), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7–21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2–18]. At 36 weeks, 29 (81%; 95% CI 65–90) patients achieved CR, and 5 (14%; 95% CI 6–29) patients achieved partial response. During a median follow-up of 38 months (range, 9–66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity.Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further.UMIN 000002210.