BACKGROUND: Pre-biopsy multiparametric magnetic resonance imaging (mpMRI) of the prostate is used to conduct targeted prostate biopsy (TB), guided by ultrasound and registered (fused) to the MRI. Systematic biopsy (SB) continues to be used together with TB or in mpMRI-negative patients. There is insufficient evidence on how to use SB to inform clinical decision-making in the mpMRI era. The purpose of this study was to estimate the effect of prostate volume and number of SB cores on sampling clinically significant prostate cancer (csPCa) using a simulation method based on clinical data. METHODS: SBs were simulated using data from 42 patients enrolled in a transrectal ultrasound robot-assisted biopsy trial. Linear mixed models were used to examine the relationship between the number of SB cores and prostate volume on 1) clinically significant cancer detection probability (csCDP) and 2) percent of mpMRI depicted regions of interest (ROIs) sampled with the SB. RESULTS: Median values and interquartile range (IQR) were 47.16 cm CONCLUSIONS: The effect of the number of SBs performed on detecting csPCa varies largely with gland volume. The common 12-core SB can achieve adequate cancer detection and sampling of ROIs in smaller glands, but not in larger glands. In addition to TB or in mpMRI-negative patients, the number of SB cores can be adjusted to prostate volume. Performing 12-core SB alone in ≥60 cm