Systemic chemotherapy with currently available agents has not improved survival for patients with hormone refractory prostate cancer (HRPC), consequently, the evaluation of new agents is warranted. Topotecan is a specific inhibitor of topoisomerase I with broad antitumor activity in preclinical studies. The purpose of this phase II trial was to determine the objective response rate of topotecan administered as a 30 minute infusion for five consecutive days in men with metastatic HRPC. Thirty-four evaluable patients were treated with topotecan 1.1-1.5 mg/m2 as a 30 minute infusion daily for five days, repeated every three weeks until disease progression or unacceptable toxicity. Response was assessed with a combination of standard solid tumor response criteria and the serum prostate specific antigen (PSA) for patients with bidimensionally measurable disease, and by serial measurements of the PSA in patients with bone only (evaluable) disease. One of 13 patients (7.6%) with measurable soft tissue disease had a PR in nodal sites. Of 21 patients with only osseous metastases, 1 (4.7%) had improvement in bone scan. Six of the 34 evaluable patients (17.6%) had the serum PSA decrease by > or = 50% and 2 (5.8%) had PSA decreases of > or = 75%. Toxicity was chiefly hematologic with 66% of patients experiencing Grade 3 or 4 granulocytopenia. Thirty-nine percent of cycles required a delay to allow for hematologic recovery and ten patients required red cell transfusions. Non-hematologic toxicity, mainly nausea and alopecia, was mild. Topotecan administered at this dose and schedule has limited activity in patients with HRPC. Further trials of topo I inhibition in HRPC should utilize alternative schedules of topotecan (e.g., prolonged infusion) or other camptothecin analogs with more potent topo I inhibitory activity.