Abstract Objectives To develop and test zone-specific prostate-specific antigen density (sPSAD) combined with PI-RADS to guide prostate biopsy decision strategies (BDS). Methods This retrospective study included consecutive patients, who underwent prostate MRI and biopsy (01/2012–10/2018). The whole gland and transition zone (TZ) were segmented at MRI using a retrained deep learning system (DLS; nnU-Net) to calculate PSAD and sPSAD, respectively. Additionally, sPSAD and PI-RADS were combined in a BDS, and diagnostic performances to detect Grade Group ≥ 2 (GG ≥ 2) prostate cancer were compared. Patient-based cancer detection using sPSAD was assessed by bootstrapping with 1000 repetitions and reported as area under the curve (AUC). Clinical utility of the BDS was tested in the hold-out test set using decision curve analysis. Statistics included nonparametric DeLong test for AUCs and Fisher-Yates test for remaining performance metrics. Results A total of 1604 patients aged 67 (interquartile range, 61–73) with 48% GG ≥ 2 prevalence (774/1604) were evaluated. By employing DLS-based prostate and TZ volumes (DICE coefficients of 0.89 (95% confidence interval, 0.80–0.97) and 0.84 (0.70–0.99)), GG ≥ 2 detection using PSAD was inferior to sPSAD (AUC, 0.71 (0.68–0.74)/0.73 (0.70–0.76); p < 0.001). Combining PI-RADS with sPSAD, GG ≥ 2 detection specificity doubled from 18% (10–20%) to 43% (30–44%; p < 0.001) with similar sensitivity (93% (89–96%)/97% (94–99%); p = 0.052), when biopsies were taken in PI-RADS 4-5 and 3 only if sPSAD was ≥ 0.42 ng/mL/cc as compared to all PI-RADS 3-5 cases. Additionally, using the sPSAD-based BDS, false positives were reduced by 25% (123 (104–142)/165 (146–185); p < 0.001). Conclusion Using sPSAD to guide biopsy decisions in PI-RADS 3 lesions can reduce false positives at MRI while maintaining high sensitivity for GG ≥ 2 cancers. Clinical relevance statement Transition zone-specific prostate-specific antigen density can improve the accuracy of prostate cancer detection compared to MRI assessments alone, by lowering false-positive cases without significantly missing men with ISUP GG ≥ 2 cancers. Key Points • Prostate biopsy decision strategies using PI-RADS at MRI are limited by a substantial proportion of false positives, not yielding grade group ≥ 2 prostate cancer. • PI-RADS combined with transition zone (TZ)-specific prostate-specific antigen density (PSAD) decreased the number of unproductive biopsies by 25% compared to PI-RADS only. • TZ-specific PSAD also improved the specificity of MRI-directed biopsies by 9% compared to the whole gland PSAD, while showing identical sensitivity.