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 starting 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.