Objectives: To define if less number of cores would be sufficient to diagnose prostate cancer (PCa) in men with PSA levels >20 ng/ml and to reveal the cancer detection rates in this population. Methods: The data of the men who had 12-core prostate biopsy with a PSA value >20 ng/mg were reviewed. We recorded age, prostate volume, PSA level, and pathology report findings. Patients grouped according to PSA levels and compared for PCa detection rates, and several parameters. We created 16 prostate biopsy scenarios (S1-S16) and applied these to our database to find out the best biopsy protocol to detect PCa. Results: A total of 336 patients with a mean age of 70.5 (47-91) years were included. Mean PSA level was 190.6 (20-5474) ng/ml. PCa detection rates were 55.3%, 81.0%, and 97.7% in patients with PSA levels 20-49.99, 50-99.99, and >= 100 ng/ml, respectively. PSA level was correlated to clinically more important digital rectal examination findings. We selected 2 cores in S1-S6, 4 cores in S7-S12, and 6 cores in S13-S16. We calculated the sensitivity of each scenario and found that all scenarios in PSA Group 3 had a sensitivity >95%. In Group 2, S8, S10, S13, and S14 and in Group 1, only S14 had sensitivity >95%. Conclusions: It is not necessary to take 10-12 core biopsy samples in men with PSA levels >20 ng/ml. We recommend taking 2, 4, and 6 samples for patients with PSA levels >= 100 ng/ml, 50-99.99 ng/ml, and 20-49.99 ng/ml, respectively.