Purpose: The goals of this study were to define the efficacy and toxicity of doxorubicin and dose-escalated cyclophosphamide (Cy) along with granulocyte colony-stimulating factor (G-CSF) in the treatment of hormone-refractory prostate cancer (HRPC), to determine the maximal-tolerated dose (MTD) of Cy in this regimen, and to evaluate the impact of prior pelvic irradiation (XRT) on MTD and toxicity. Patients and Methods: Thirty-five patients were treated every 21 days with fixed-dose doxorubicin (40 mg/m2) and Cy 800 to 2,000 mg/m2 (in a cohort dose-escalation schema) along with G-CSF. Results: Five of 15 patients (33%) with measurable disease obtained an objective response. Sixteen of 35 patients (46%) had a greater than 50% decrease in prostate-specific antigen (PSA) level (95% confidence interval [CI], 28.8% to 63.4%). Ten of 35 patients (28.6%) had a greater than 75% decrease in PSA level. The median survival time was 11 months. The median survival duration of patients with a greater than 50% decrease in PSA level was 23 months, versus a median survival time of 7 months in patients without a PSA response (P = .02). Although 33% of cycles were associated with grade 4 neutropenia, febrile neutropenia occurred in only 7.8% of all cycles. Thrombocytopenia and anemia were rare. Nonhematologic toxicity was minimal. Patients who had received prior pelvic XRT had a lower Cy MTD, but their hematologic toxicity was not appreciably different. Conclusion: This is a well-tolerated, active regimen for the treatment of HRPC. Toxicity was not different in patients with prior pelvic XRT, although these patients had a lower MTD.