Objective: The purpose of this study was to define the response rate and toxicity of topotecan in patients with ovarian cancer resistant to first- line therapy. Methods: Twenty patients with advanced or recurrent ovarian cancer were enrolled in a phase I/II protocol, and an additional 16 patients were treated following protocol closure at Washington University Medical Center. The starting dose of topotecan was 1.25 mg/m2/day given intravenously over 30 min for 5 consecutive days. Patients were eligible for response evaluation if they completed more than one cycle of topotecan. All patients were evaluated for toxicity. Results: Of 28 patients eligible for response evaluation, 26 were resistant to both platinum and paclitaxel prior to treatment with topotecan. There were four partial responders and no complete responders for a total response rate of 14% (95% confidence interval: 4 to 33%). All responders had exhibited primary resistance to both platinum and paclitaxel. Myelotoxicity was the major toxicity, with 92% of patients experiencing Gynecologic Oncology Group (GOG) grade 3 or 4 neutropenia and 67% experiencing GOG grade 3 or 4 thrombocytopenia. Other toxicity was minimal and easily managed. Fifty percent of patients receiving more than one cycle of topotecan tolerated a dose equal or greater to the staring dose. Conclusions: Topotecan exhibits activity in patients with ovarian cancer resistant to both platinum and paclitaxel. Further study is warranted in less heavily pretreated patients and in combination with other chemotherapeutic agents.