Abstract Background Index lesion‐focused ipsilateral systematic biopsy (iSB) has been proposed as a core‐reduction alternative to MRI‐targeted biopsy combined with systematic biopsy (TB + SB) for prostate cancer, but prospective multicenter validation is limited. Methods This prospective multicenter trial (NCT06584279) enrolled biopsy‐naive men with Prostate Imaging Reporting and Data System (PI‐RADS) ≥4 lesions or PI‐RADS 3 plus prostate‐specific antigen (PSA) density ≥0.15 ng/mL/cm 3 . All underwent MRI‐targeted biopsy (≥2 cores/lesion) with 12‐core SB. Through core‐level reclassification, the authors simulated TB + iSB (targeted biopsy combined with index lesion‐ipsilateral systematic biopsy). The primary outcome was cancer detection rate (CDR) of clinically significant prostate cancer (csPCa; Grade Group ≥2) with a noninferiority margin of –3%. Secondary outcomes included clinically insignificant prostate cancer (cisPCa; Grade Group 1) detection and pathological concordance after radical prostatectomy. Results Among 564 men (median age, 69 years; median PSA, 7.3 ng/mL), TB + iSB demonstrated a noninferior csPCa CDR versus TB + SB (40.78% vs. 42.38%; difference, –1.6 percentage points; 95% CI, –2.69 to –0.50), with the lower bound above the –3% noninferiority margin. The cisPCa CDR was slightly lower with TB + iSB than with TB + SB (13.83% vs. 14.36%; difference, –0.53 percentage points; 95% CI, –2.01 to 0.92). Among 189 surgical patients, pathological concordance was similar, whereas upgrading was numerically more frequent and downgrading numerically less frequent under simulated TB + iSB. Conclusions TB + iSB met the prespecified noninferiority criterion for csPCa detection relative to TB + SB and may represent a promising core‐reduction strategy in transperineal MRI‐guided biopsy, although the full protocol still provided additional contralateral information.