To evaluate the efficacy and safety of neoadjuvant docetaxel and estramustine in patients with high-risk, newly diagnosed, prostate cancer. Eligible patients had prostate cancer with one or more of the following criteria: clinical Stage T2b or greater, prostate-specific antigen (PSA) of 15 ng/mL or greater, and/or Gleason score of 8 to 10. Chemotherapy consisted of docetaxel (70 mg/m 2) on day 1 and estramustine (280 mg three times daily) on days 1 to 3 every 21 days for three to six courses. This was followed by local therapy, as deemed appropriate. Twenty-one patients with a median age of 60 years, median PSA level of 16.1 ng/mL (range 2.4 to 175), and median baseline testosterone of 3.4 ng/mL were enrolled. Seven patients met one of the inclusion criteria, 10 met two, and 4 met three. The Gleason score was 8 or greater in 14 patients. A median of five cycles of chemotherapy was delivered. The most frequent high-grade toxicities were grade 3 (8 patients) and 4 (1 patient) neutropenia and deep venous thrombosis (grade 3 in 2 patients) before institution of low-dose warfarin. All patients responded as determined by protocol-defined criteria. Ten patients underwent radical prostatectomy, with negative surgical margins in 7 patients, and 11 received radiotherapy with negative preradiotherapy biopsies in 2. Induction docetaxel and estramustine is well tolerated and feasible in patients with newly diagnosed, high-risk prostate cancer. This combination is active; however, its efficacy relative to hormonal therapy will require a controlled randomized trial.