Objectives. To determine, in a prospective study, the prostate-specific antigen (PSA) response to finasteride challenge in men with a serum PSA greater than 4 ng/mL who had undergone previous biopsy. Patients with a serum PSA level greater than 4 ng/mL who have undergone repeated prostate biopsy with prostate cancer (CaP) that was not detected present a diagnostic dilemma. The magnitude of PSA reduction after administration of finasteride has been well documented. In addition, doubling of the PSA value after 1 year of finasteride has been touted to be a more useful paradigm for diagnosing CaP than PSA alone. Methods. Thirty-eight men with a baseline serum PSA level greater than 4 ng/mL and a normal digital rectal examination who had been previously biopsied a minimum of two times, with CaP not detected, were given 5 mg finasteride daily. The PSA level was measured at 6 and 12 months with repeat transrectal ultrasonography and biopsy (12 cores) performed at 1 year. Changes in prostate volume, serum PSA, PSA density, and the incidence of CaP at 1 year were assessed. Results. The mean age of the group was 60.5 years (±7.6). For the group, the average number of previous biopsies performed was 2.9 (range 2 to 6). The baseline PSA level for the entire group was 6.32 ng/mL (±3.2), and the baseline prostate volume was 37.3 cm3 (±12.4). At 1 year, the PSA level had decreased to 3.73 ng/mL (-41.0%), and the prostate volume had decreased to 30.4 cm3 (-18.5%). In the 11 men (29%) in whom CaP was detected, the serum PSA decreased from 7.3 to 5.2 ng/mL (-28.8%) and the prostate volume decreased from 37.3 to 32.3 cm3 (-13.4%). CaP was detected in 0 of 10 men with a serum PSA decrease of 50% or higher, in 6 (32%) of 19 men with a PSA decrease between 33% and 50%, and in 5 (56%) of 9 men who had a PSA decrease of less than 33%. Conclusions. The data in this preliminary study suggest that the magnitude of change in serum PSA after 1 year of finasteride challenge may be useful in diagnosing CaP in patients with elevated PSA levels and prior negative prostate biopsy.