In other Gynecologic Oncology Group (GOG) studies, ifosfamide demonstrated antineoplastic activity against ovarian epithelial tumors, squamous carcinomas of the cervix, uterine sarcomas, and trophoblastic disease. Responses were also observed in 15% of patients with endometrial adenocarcinoma previously exposed to chemotherapy. This is a phase II trial of ifosfamide in patients with chemotherapy-naive advanced or recurrent endometrial adenocarcinoma. Thirty-seven patients with advanced adenocarcinoma of the endometrium recurrent after surgery and/or radiotherapy were treated with ifosfamide 1.2 g/m2 intravenously daily for 5 days every 4 weeks and mesna 300 mg/m2 intravenously every 4 hr for 3 doses daily for 5 days with each course. Three patients were ineligible--one due to a second primary, one did not have an endometrial primary, and the other because of wrong cell type. One patient was inevaluable for response; thus, 33 were evaluable for response. All patients had undergone hysterectomy and 24 had received radiotherapy before entering the trial. Eleven had GOG performance status of 0, 18 had a status of 1, and 4 had performance status of 2. Median age was 68 years (range, 41-86 years). Grade 3 or 4 neutropenia occurred in eight patients each and grade 3 thrombocytopenia was observed in one patient. One patient had a grade 4 neurotoxicity. Complete responses were observed in two patients (6.1%) and partial responses in six (18.2%) for an overall response rate of 24.3%. Ifosfamide in this dose and schedule is an active drug in the treatment of patients with advanced or recurrent adenocarcinoma of the endometrium.