OBJECTIVE: To compare the efficacy and tolerability of peripheral androgen blockade using combined low-dose flutamide plus finasteride vs low-dose flutamide monotherapy for treating biochemical relapse after the definitive management of prostate adenocarcinoma. PATIENTS AND METHODS: Fifty-six men treated for biochemical relapse of prostate cancer were enrolled prospectively in a phase II trial at the Walter Reed Army Medical Center from 1997 to 2001. Thirty-six men were treated with flutamide (125 mg twice daily) and finasteride (5 mg twice daily), and 20 men received low-dose flutamide only after biochemical recurrence (prostate-specific antigen, PSA, level > or =0.4 ng/mL). Cox proportional hazards analyses were used to compare the risk of progression between the groups. RESULTS: Patients on combined and monotherapy had a median follow-up of 54 and 43.5 months, respectively. Seven men (19%) in the combined arm remain in the study with no progression, while five (25%) on monotherapy continue and are progression-free. Men on combined therapy had a greater decrease in their PSA level (P = 0.002). Multivariate analysis showed that men on combined therapy had significantly less risk of progression than men on monotherapy (hazard ratio 0.21, 95% confidence interval 0.07-0.63, P = 0.005). There was no significant difference in the frequency of side-effects between the groups. Toxicities were reported to be mild. CONCLUSIONS: Our analysis suggests the therapeutic value of low-dose flutamide alone or combined with finasteride as first-line agents in a possible graduated approach for treating PSA-only recurrent prostate cancer. Due to unwanted metabolic effects associated with traditional hormonal agents, phase III trials comparing both regimens with current therapies are warranted.