Objective: Women older than 40 years develop gestational trophoblastic neoplasia (GTN) after a hydatidiform mole (HM) more often than do younger women. Therefore, in elderly women, primary hysterectomy has been advocated as first-line treatment. The aim of the present study was to evaluate whether hysterectomy could reduce the incidence of GTN after a diagnosis of HM. Methods: Seventy-six of 442 patients referred to our unit for an HM between 1994 and 2015 were older than 40 years old. Among these, 12 patients were treated by primary hysterectomy. We compared clinical features, serum human chorionic gonadotrophin (hCG), incidence of GTN, and further treatments in these patients and in those who underwent evacuation and serum hCG monitoring, using univariate and multivariate analyses. Results: Patients treated by primary hysterectomy all had a diagnosis of a complete or invasive HM, had more hyperemesis than did control subjects (82% vs 37%, P = 0.008), and had an increased uterine volume (100% vs 41%, P = 0.001). Seven of them developed a subsequent GTN, whereas 5 patients achieved complete remission of disease after surgery (58% vs 30%, P = 0.094). All the patients who developed a GTN after surgery showed lower hCG levels than did control subjects (mean, 671.4 [SD, 1178.4] IU/L vs 23,919.4 [SD, 34,284.9] IU/L; P = 0.005), but there were no significant differences in the amount and type of chemotherapy needed to achieve remission. Conclusions: Primary hysterectomy after 40 years old in women affected by HM does not reduce the incidence of GTN and amount of chemotherapy. Although further studies are needed to confirm these results, a careful hCG monitoring should be recommended in these high-risk patients. Copyright © 2017 by IGCS and ESGO.