Preclinical data suggest that small quantities of estramustine phosphate are synergistic with taxanes and may be useful in the treatment of hormone-refractory prostate cancer. The current trial was designed to reduce the duration of exposure to estramustine phosphate, which carries with it the risk of anorexia and gastrointestinal, cardiovascular, and thromboembolic toxicity during long-term treatment. Patients with histologically confirmed adenocarcinoma of the prostate showing evidence of progressing disease 4 to 6 weeks after antiandrogen withdrawal were enrolled into the study. Patients may have received up to two prior chemotherapy regimens. Patients received estramustine phosphate 280 mg orally every 6 hours for a total of five doses (24-hour exposure), docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) 70 mg/m2 intravenously over 1 hour, coumadin 2 mg orally every day, and dexamethasone as premedication for docetaxel. Cycles were repeated every 21 days, up to a maximum of 6. Of the 18 evaluable patients, seven showed more than 50% declines in prostate-specific antigen for a duration > or =4 weeks; two of eight patients had soft tissue partial responses. Nine of 11 had improvement in pain and/or urinary symptoms. In a total of 98 cycles, grade 3 toxicities observed included leukopenia (N = 7), neutropenia (N = 6), fatigue (N = 13), headache (N = 1), local skin reactions after extravasation (N = 2), nail changes (N = 1), diarrhea (N = 2), and hyperglycemia (N = 3); grade 4 toxicities included neutropenia/fever requiring admission (N = 2), leukopenia (N = 2), and neutropenia (N = 6). No thromboembolic complications were seen. All toxicities were reversible within 1 week after occurrence. Thus, preliminary evidence suggests that in this heavily pretreated patient population 1-day treatment with an estramustine/docetaxel combination is active and has acceptable toxicity.