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Objectives: To evaluate the clinically-significant prostate cancer (csCaP) detection rate of systematic (SBx) vs. targeted biopsy (TBx), after accounting for the overlapping systematic cores within the MRI regions of interest.Materials and Methods: We identified 398 consecutive men who underwent both transperineal systematic and targeted biopsy between January 2015 to January 2019. We reclassified overlapping systematic cores in the MRI regions of interest as target cores. The detection rates of SBx and TBx were compared using McNemar's test.Results: Detection rate of csCaP (grade group ≥2) was 42% (168/398). Median number of systematic and targeted cores were 23 (IQR 19-29) and 9 (IQR 6-12) respectively. A median of 3 (IQR 2-4) overlapping systematic cores were reclassified as targeted cores. After accounting for overlap, csPC detection rate on SBx decreased from 37% and 21% while the csCaP detection rate of TBx increased from 34% to 39% (both P < 0.001), with TBx having a better detection rate (39% vs. 21%, P < 0.001). A previous negative biopsy was associated with a lower risk of having csCaP on non-targeted SBx (OR 0.27, 95% CI: 0.12 - 0.58, P = 0.001). Only 5% (13/243) of those who had no cancer detected on TBx had csCaP on non-targeted SBx compared to 45% (70/155) of those who had csCaP on TBx (P< 0.001).Conclusions: The utility of SBx in detecting csCaP decreases after accounting for overlap into the MRI region of interest, especially in men with a prior negative biopsy. Overlapping systematic cores improve the csCaP detection rate on TBx. [ABSTRACT FROM AUTHOR]