We present a 46-year-old patient who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy for persistent trophoblastic disease. Single-agent chemotherapy with alternate methotrexate 1 mg/kg/day and leucovorin 0.1 mg/kg for 8 days was instituted on the first postoperative day. Various adverse symptomatology developed, culminating in a unique side effect, polyserositis. To the best of our knowledge, the wide spectrum of side effects, the short time lapse after onset of chemotherapy, and their severity are uncommon in a patient receiving her first chemotherapeutic treatment with MTX.