Androgen deprivation displays the mean therapy of advanced stage prostatic cancer. The development of hormone-resistant disease leads to a fatal tumor progression. High-dose fosfestrol (diethylstilbestrol disphosphate) has been suggested to circumvent hormone resistance and to induce a direct cytotoxic effect. Twenty-one patients with hormone-refractory prostate cancer were enrolled in a phase I trial of continuous infusion of high, daily escalating dose of fosfestrol. Fosfestrol was given in a 3.5 hr infusion in 0.9% normal saline at a starting dose of 1.5 g/d. The dose was increased daily in the same patient according to the following schedule: 1.5, 1.8, 2.4, 3.0, 3.6, 3.9, 4.5, 5.1 and 5.7 g/d. The duration of the infusion was prolonged to 7 or 10.5 hr, if a major side effect occurred. There was neither hematological nor cardiovascular toxicity. The main dose-limiting toxicities were nausea/vomiting in 17 patients, edema in 2 patients, and more than 5% weight gain in 3 patients. The planned maximal dose was reached in 10 patients during a 3.5 hr infusion, and in 3 additional patients, after infusion prolongation. Seven patients experienced a subjective improvement. Prostatic acid phosphatase and prostatic specific antigen decreased in 4 out of 11 and in 7 out of 12 patients, respectively. The suggested dose to phase II trial is 4 g/d in 3.5 hr infusion for a duration of up to 10 days. © 1994 Wiley-Liss, Inc.