High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a premalignant change in the prostate that indicates increased risk of the subsequent development of prostate adenocarcinoma. Prior studies have suggested that androgen deprivation therapy causes a regression of HGPIN. We therefore conducted a chemoprevention trial assessing the efficacy of flutamide in reducing the rate of prostate adenocarcinoma development in men with HGPIN. Men with biopsyproven HGPIN but no evidence of prostate adenocarcinoma were randomized in a double-blind manner to either flutamide 250 mg/d or a placebo. Treatment was continued for 1 year. Repeat biopsies were obtained at 12 and 24 months. Quality of life and toxicities related to treatment were also measured. Sixty patients were randomized and began therapy with either flutamide or placebo. At 1 year, 14% of men receiving flutamide and 10% of men receiving placebo had developed prostate adenocarcinoma. Flutamide-associated toxicities were mild to moderate in severity. Quality-of-life measures did not show any differences between the 2 groups. This study showed no evidence of benefit from flutamide as a chemoprevention agent in men with HGPIN.