Prolonged oral etoposide is an active regimen in small and nonsmall cell carcinoma of the lung, carcinomas of the breast and ovary, germ cell tumors, and in lymphoma. A Phase II trial was conducted by the Gynecologic Oncology Group to determine its activity in endometrial carcinoma. Twenty-six patients with advanced or recurrent endometrial carcinoma were entered into study; one patient was ineligible because of an incorrect cell type. The remaining eligible patients were treated with etoposide at a starting dose of 50 mg/m2/day (30 mg/m2/day with prior radiotherapy) for 21 days. Based on hematologic toxicity, a dose escalation to a maximum dose of 60 mg/m2/day was prescribed. Twenty-two patients were evaluable for response and 25 were evaluable for toxicity. Fourteen had received prior radiotherapy and 24 had received prior chemotherapy. A median of two courses were given (range, 1-10). Grade 3 or 4 leukopenia occurring in 52% was the most common complication (grade 3, 36%; grade 4, 16%). Grade 4 thrombocytopenia occurred in 16% of patients. There were no objective responses including four patients with serous papillary carcinoma. This regimen is not significantly active as second-line therapy in endometrial carcinoma.