Gestational trophoblastic disease (GTD) commonly occurs in reproductive females, but is extremely rare in perimenopausal females. In this study, we reported a case of hydatidiform mole in a 48-year-old perimenopausal female admitted due to a giant uterine mass of 28 weeks’ gestational size. The serum human chorionic gonadotropin (HCG) level ranged from 944 to 1,286 mIU/mL before treatments. The signs of preeclampsia and hyperthyroidism were relatively prominent. Hysterectomy was performed and chemotherapy was scheduled when the serum HCG level remained at a plateau, about 528 mIU/mL. The symptoms of preeclampsia and hyperthyroidism were relieved after treatment. Accordingly, we concluded that GTD could occur in perimenopausal woman and hysterectomy usually is the optimal treatment.