Objectives: To evaluate the diagnostic value of saturation prostate biopsy in patients with prostate-specific antigen (PSA) greater than 10 ng/mL, PSA velocity greater than 0.75 ng/mL/year, free PSA ratio less than 0.2, and at least 3 sets of negative biopsy specimens. Methods: Twenty-seven patients underwent the procedure with the use of a transrectal approach under general or regional anesthesia. A systematic coverage of the peripheral zone was accomplished by maintaining a fixed distance between punctures (5 mm). In addition, multiple cores were obtained from the transition zone bilaterally, bladder neck, and midline according to a strict preplanned template. Results: The mean number of cores obtained per patient was 61.7 ± 9.5 (range 41 to 76). Average PSA was 19.4 ± 8.5 ng/mL (range 10.1 to 49). Prostate cancer (Gleason score 3+3) was found in 3 patients (11.1%). All 3 patients who received a diagnosis of cancer had minimal disease affecting less than 1% of a single core sampled from the peripheral zone. Two patients were designated for watchful waiting and 1 patient chose radical prostatectomy. His pathologic specimen contained carcinoma of prostate (Gleason 3+3) in less than 1% of the total prostate volume. All patients were discharged within 24 hours after the procedure. Asymptomatic bacteremia was documented in 1 patient. Two patients had epididymitis develop and were treated conservatively. Conclusions: According to our findings, saturation prostate biopsy has low diagnostic yield in patients who previously had at least 3 sets of negative traditional biopsy specimens. In all the cases, that prostate cancer was found, it had histologic features consistent with biologically insignificant disease.