BACKGROUND: Even in castration-resistant prostate cancer (CRPC), the androgen pathway remains biologically relevant. In preclinical models, androgen therapy for CRPC leads to growth arrest, apoptosis, and tumor shrinkage. OBJECTIVE: This study sought to determine the toxicity and feasibility of a testosterone therapy in early CRPC. DESIGN, SETTING, AND PARTICIPANTS: Prostate cancer patients with progressive disease following androgen ablation, antiandrogen therapy, and withdrawal and no to minimal metastatic disease who were followed at the University of Chicago were randomized to treatment with three doses of transdermal testosterone. INTERVENTION: Patients were treated with transdermal testosterone at 2.5, 5.0, or 7.5mg/day. MEASUREMENTS: Toxicity, prostate-specific antigen (PSA), imaging, quality of life (QoL), and strength were monitored. Treatment was discontinued for significant toxicity, clinical progression, or a 3-fold increase in PSA. RESULTS AND LIMITATIONS: Fifteen men with a median age of 73 yr (range: 62–92) and a median PSA of 11.1ng/ml (range: 5.2–63.6) were treated. Testosterone increased from castrate to median concentrations of 305ng/dl, 308ng/dl, and 297ng/dl for dosages of 2.5mg/day (n=4), 5.0mg/day (n=5), and 7.5mg/day (n=5), respectively. One patient was taken off of the study at 53 wk due to grade 4 cardiac toxicity. There were no other grade 3 or 4 toxicities related to the study medication, and the grade 2 toxicities were minimal. Only one patient experienced symptomatic progression, and three (20%) patients demonstrated a decrease in PSA (largest was 43%). Median time to progression was 9 wk (range: 2–96), with no detectable difference in the three dose cohorts. There was no significant improvement in QoL, and there was a borderline statistically significant improvement in hand-grip strength with treatment. The study was limited by sample size, single arm, and variability of baseline patient characteristics. CONCLUSIONS: Testosterone is a feasible and reasonably well-tolerated therapy for men with early CRPC. A larger, randomized trial is under way to further characterize efficacy and impact on QoL measures.