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Background and Objectives: Multiparametric MRI (mpMRI) has improved prostate cancer (PCa) detection, but the added value of cognitive fusion (CF) over systematic biopsy (SB) remains debated. This prospective study evaluated the diagnostic performance of SB, CF, and their combined use in patients with Prostate Imaging and Reporting Data System (PI-RADS) ≥3 lesions. Materials and Methods: A total of 282 patients underwent mpMRI followed by both SB and CF biopsy. Results: PCa was diagnosed in 154 patients. SB detected 112 cancers (24 ISUP 1 (International Society of Urological Pathology), 88 ISUP ≥ 2), and CF detected 135 cancers (16 ISUP 1, 119 ISUP ≥ 2), while the combined approach detected all 154 cancers (9 ISUP 1, 145 ISUP ≥ 2). CF identified 42 cancers missed by SB, whereas SB identified 19 cancers not detected by CF. CF upgraded 38 patients from low-risk to intermediate-risk (23)/high-risk (15) categories, while SB underestimated disease severity in 41 cases. No major biopsy-related complications were recorded. Conclusions: CF biopsy outperformed SB in detecting clinically significant PCa and improved risk stratification, while the combined approach provided the highest overall diagnostic performance, supporting its use in contemporary PCa assessment.