Hormone-refractory prostate cancer is the terminal step in the natural history of prostate cancer. To date, no chemotherapeutic agents have been shown to impact clinical outcome at this stage. Recently, the Food and Drug Administration approved the combination of mitoxantrone and prednisone based solely on its superior palliative effects as compared to steroids alone in 2 randomized trials. Progress in biologically driven drug development has led to the identification of several estramustine-based regimens that, although based on single institution experience, appear to have at least a comparable but very promising level of activity in hormone-refractory prostate cancer patients. One such combination, estramustine plus docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), is particularly attractive because of its convenient schedule and side effect profile. To objectively assess the therapeutic benefit of this combination, the Southwest Oncology Group is initiating a randomized phase III trial comparing estramustine and docetaxel with the standard arm of mitoxantrone and prednisone using time to progression and survival as the primary end points. Secondary end points will include toxicity profiles, assessments of quality of life parameters, and magnitude of decline of prostate-specific antigen levels between the two treatment arms.