Background: The value of saturation prostate biopsy (SPBx) in patients without biopsy history remains controversial. Materials and Methods: A total of 644 consecutive suspected prostate cancer (PCa) cases without biopsy history were retrospectively grouped as 24-core transperineal SPBx (n = 368) guided by coaxial needle and prostate transperineal biopsy (PBx) (systematic 14-core scheme, n = 276). PCa detection rates were compared based on prostate-specific antigen (PSA) levels, PSA density (PSAD), and Gleason scores. Complications associated with those procedures were assessed. Results: Coaxial SPBx was superior to the 14-core scheme for overall PCa detection rates (39.67% vs. 24.64%), at PSA levels of 4.1u10.0 ng/ml (37.37% vs. 23.48%) or 10.1u20.0 ng/ml (43.31% vs. 27.21%), and PSAD <0.15 (47.80% vs. 29.23%) or 0.15u0.24 (34.07% vs. 20.93%) (all P < 0.05). In patients with positive biopsy, the rates of nonclinically significant PCa were comparable between the two biopsy groups. Conclusions: Transperineal coaxial needle SPBx as the initial scheme improves PCa detection compared with initial systematic 14-core PBx, without increasing complications and overdiagnosis.