Introduction: We retrospectively compared 6- and 12-core prostate biopsies in Taiwanese men and evaluated the impact of prostate volume (PV), prostate-specific antigen (PSA), and PSA density (PSAD) on the prostate cancer detection rate (PCDR). Patients and Methods: 1,086 consecutive patients with a total PSA of 4.1–20.0 ng/ml and/or abnormal digital rectal examination undergoing first-time transrectal ultrasound-guided biopsy were included. Group I patients (n = 562) underwent sextant biopsy and group II patients (n = 524) underwent sextant biopsy with an extra three lateral cores on both sides. The patients were further stratified into subgroups according to PV (cut-off: 35 ml), PSA (cut-off: 10.0 ng/ml), and PSAD (cut-off: 0.2). Results: Prostate cancer was diagnosed in 228/1,086 (21.0%) patients. The PCDR was higher in group II (23.7%) than group I (18.5%). 12-Core biopsy yielded a significantly higher PCDR than 6-core biopsies in patients with PV >35 ml, PSA 4.1–10.0 ng/ml, PSAD ≤0.20, but not in patients with PV ≤35 ml, PSA 10.1–20.0 ng/ml, PSAD >0.20. Conclusions: 12-Core biopsy yielded a significantly higher PCDR in Taiwanese men with a total PSA of 4.1–20.0 ng/ml, especially in patients with PSA 4.1–10.0 ng/ml, PSAD ≤0.20, and PV >35 ml.