Background <p>Comparisons between the transperineal (TP) and the transrectal (TR) approach for prostate biopsies in detecting cancer have been reported; however, there are no reports comparing the cancer detection rates using an anatomical approach. In this study, magnetic resonance imaging and ultrasonography (MRI/US) fusion prostate biopsies were compared between the TP and the TR approaches for detecting cancer at the target sites.</p> Methods <p>The MRI/US fusion prostate biopsies were performed between November 2016 and October 2021. There were 251 and 200 patients in the TP and TR groups, respectively. Age, serum prostate specific antigen level, prostate volume, number of biopsies, target site (anterior, posterior, apex, lateral, base, middle), cancer detection rate, and the Gleason Grading Group classification were examined.</p> Results <p>There were 154 and 101 target sites in the TP and TR groups for Prostate Imaging Reporting and Data System (PI-RADS) category 4–5. Significantly higher cancer detection rates were noted for PI-RADS category 4–5 lesions than for category 3 lesions in both the TP and TR groups (<i>p</i> &lt; 0.001). The cancer detection rates for category 4–5 lesions in the TP and TR groups were 94.4% and 73.3% (<i>p</i> = 0.036), 92.3% and 64.7% (<i>p</i> = 0.017), 69.4% and 93.3% (<i>p</i> = 0.055), and 66.7% and 89.3% (<i>p</i> = 0.010) at the anterior, apex, lateral, and posterior sites, respectively.</p> Conclusions <p>The cancer detection rate was significantly different between the TP and TR groups at the anterior, apex, and posterior sites. These differences may be due to the sampling deflection of the needle on the posterior site in the TP group and on the apex and anterior sites in the TR group. These results suggest that urologists should be mindful of the benefits for each patient by considering the advantages with each approach.</p>