Recently, the use of targeted biopsy has been subject to critics, as it has been speculated that targeted biopsy might lead to overdiagnosis of clinically significant prostate cancer (PCa). In this study, we tried to evaluate whether targeted sampling in patients with organ-confined disease and ISUP 2 disease was associated with downgrading of the prostatectomy specimen, hence, leading to an unnecessary treatment, in terms of radical surgery. We relied on a prospectively-maintained multi-institutional database and identified 1293 patients with ISUP 2 disease on targeted biopsy only. Median (IQR) patients’ age at diagnosis was 65 (60, 70) years. Median PSA was 6.8 (5.0, 9.6) ng/ml. Overall, only 33 (2.6%) patients presented downgrading on their RP specimens. Patients who experienced downgrading were biopsied more frequently trans-rectally, had a lower total tumor length in mm and lower percentage of maximum core involvement and lower rates of cancer on systematic biopsy (all p ≤ 0.03). The strongest factors associated with reduced risk of downgrading were total tumor length, in mm, (OR: 0.71, 95% CI: 0.62,0.82, p < 0.001) and transperineal biopsy route (OR: 0.38, 95% CI: 0.14,1.00, p = 0.05).