Neoadjuvant hormonal therapy (NHT) has been extensively studied in patients undergoing radical prostatectomy and external-beam irradiation for prostate cancer. While there are a few reports in the literature on its use in men undergoing brachytherapy, little information exists about its beneficial effects in such patients. In this report, we describe the effects of NHT on prostate volume (PV) prior to seed implantation and on the prostate specific antigen (PSA) and postimplant biopsy outcomes of patients who presented with high-risk features. Hormone therapy (leuprolide and flutamide 750 mg/day) was given to 145 patients for 3 months prior to and for 3 months after permanent iodine-125 (160 Gy) or palladium-103 (115 Gy) seed implantation. Of these, 28 (19%) received NHT because of a preimplant PV >50 cc, and 117 patients received NHT because they had a PSA >10 ng/mL, Gleason score >/=7, or clinical stage >/=T(2b). All patients underwent implantation using the real-time intraoperative method, and no patients received external-beam irradiation. Of the 145 patients treated, 67 (46%) had a PSA >10 ng/mL (range 1.9-57 ng/mL; mean 12.2 ng/mL), 50 (35%) had Gleason score >/=7, and 80 (55%) had stage >/=T(2b) disease. Prostate volume was measured in 106 patients prior to NHT and 3 months later immediately prior to the seed implant. The mean PV was 50.4 cc (range 17-150 cc), whereas the mean PV after NHT was 31 cc (range 11.7-73.7 cc). The mean PV reduction was 35% (range 2%-62%). Volume reduction was compared in those patients who presented with a PV <40 cc (N = 51) and those with a PV >/=40 cc (N = 56). The mean reduction for the smaller glands was 29% (range 2%-54%) compared with 41% (range 7%-62%) for the larger glands (P < 0.05). Patients were followed for a minimum of 1 year (range 1.0-6.4; mean 2.2 years). The 4-year actuarial rate of freedom from PSA failure (PSA >1.0 ng/mL with two consecutive elevations) was 85%. There was no difference in rates of freedom from PSA failure for those with initial Gleason 2-4 (96%), 5-6 (78%), 7 (80%), or 8-9 (83%; P = 0.5). Control rates were 85% for patients with PSA </=10 ng/mL, 82% for patients with PSA 10 to 20 ng/mL, and 88% for patients with PSA >20 ng/mL (P = 0.8). There was a trend to decreased control rates with higher-stage disease (98% for T(1)-T(2a) v 68% for T(2c)), but these differences were likewise not significant (P = 0.12). The control rates for the 28 low-risk patients with enlarged prostate glands were compared with those of the 117 with high-risk features and were not different (100% v 82%; P = 0.1). There were 62 patients who agreed to eight-core prostate biopsies 2 years after implantation, and 60 (97%) were negative for tumor. This trial shows that NHT can reduce PV an average of 35% prior to seed implantation with the greatest reduction found in patients with larger prostates (41%). Hormonal therapy also appears to improve biochemical (PSA) control and local control (prostate biopsy) in patients with high-risk disease, yielding results similar to those in men with low-risk prostate cancer.