Background and purpose <p>Although cognitive fusion-targeted biopsy (CF-TB) is less invasive than systematic biopsy (SB), evidence regarding its diagnostic efficacy in metastatic prostate cancer (mPCa) remains limited. This study aimed to compare the pathological positive rates of CF-TB and SB in diagnosing mPCa.</p> Methods <p>This study included 113 patients with mPCa who underwent transperineal CF-TB 3–4 needles and 12 needles SB under the guidance of MRI /TRUS cognitive fusion in Huanxing Tumor Hospital of Chaoyang District, Beijing, from January 2019 to December 2025. The primary endpoint was the pathological positive rate. The McNemar test was used to compare the two biopsy methods.</p> Results <p>The median age was 70 years (IQR: 65-75.5), the median total PSA before biopsy was 21 ng / mL (IQR: 10.5–38.5), and the median prostate volume was 40 mL (IQR: 28–60). Among the 113 patients, 98 (86.7%) had positive digital rectal examination (DRE), and 75 (66.4%) had PI-RADS 5 lesions on mpMRI. The positive rates of CF-TB and SB were 98.2% and 96.5%, respectively. There was no significant difference in the positive detection rate between the two groups (McNemar ‘s Χ² = 0.6667, <i>P</i> = 0.414), and the consistency was as high as 94.7%. The positive rate difference between the two methods was − 1.77%, and the 95% confidence interval was [-4.5%, 1.0%].</p> Conclusion <p>In patients with DRE positive and high PSA and PI-RADS score 5, CF-TB can replace SB and avoid missed diagnosis in this specific high-risk subgroup.</p>