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Objectives: To compare the detection rates of overall prostate cancer (PCa) and clinically significant PCa (csPCa) and the median percentage of cancer per biopsy core between MRI-guided In-bore and MRI-TRUS fusion-targeted biopsy (TBx). Methods: In this retrospective study, 223 patients who underwent prostate multiparametric MRI (mpMRI) and subsequent MR-directed biopsy were included. For PCa and csPCa detection rate (DR), contingency tables were tested via the Pearson’s chi-squared to explore the variance of the outcome distribution. The percentage of cancer per biopsy core was tested with a two-tailed Mann-Withney test. Results: One hundred and seventeen and 106 patients underwent MRI-TRUS fusion or MRI In-bore TBx, respectively. 402 MRI biopsy targets were identified, of which 206 (51.2%) were biopsied with the MRI-TRUS TBx and 196 (48.8%) with the MRI In-bore TBx technique. Per-patient PCa and csPCa detection rates were 140/223 (62.8%) and 97/223 (43.5%), respectively. PCa-DR was 73/117 (62.4%) and 67/106 (63.2%) for MRI-TRUS and MRI In-Bore TBx (p = 0.9), while csPCa detection rate reached 50/117 (42.7%) and 47/106 (44.3%), respectively (p = 0.81). The median per-patient percentage of malignant tissue within biopsy cores was 50% (IQR: 27–65%) for PCa and 60% (IQR: 35–68%) for csPCa, with a statistically significant difference between the techniques. Conclusion No statistically significant difference in the detection rate of MRI In-bore and MRI-TRUS fusion TBx was found. MRI In-bore TBx showed higher per-core percentage of malignant cells. Advances in knowledge MRI In-bore biopsy might impact risk stratification and patient management considering the higher per-core percentage of malignant cells, especially for patients eligible for active surveillance or focal therapy.