Alkylating agents have been reported to yield response rates of up to 20% in hormone-refractory prostate cancer. Melphalan was studied in four small trials in which the drug was given orally. In this phase II trial, melphalan (30 mg/m2) was given intravenously every 28 days to 27 patients with hormone-refractory prostate cancer. Pharmacokinetic sampling was performed so as to describe the clearance of melphalan in this population and in an attempt to carry out pharmacodynamic modeling for toxicity and response. Prostate-specific antigen (PSA) was also assessed prospectively. No objective responses to this regimen were documented. The median survival for patients on this trial was 11.5 months. There was no correlation between drug clearance and measured creatinine clearance and no relationship between systemic exposure and toxicity. A decrease of >50% in serum PSA that was sustained for >6 weeks was documented in two patients, most notably in one patient who has survived for more than 29 months. Intravenous melphalan is not an active agent in hormone-refractory prostate cancer.