Background <p>Multiple parameters including PSA, PSAD, and PIRADS v2.1 score, are being associated in an effort to increase the overall detection rate of clinically significant prostate cancer (csPCa). This study aims to explore gray zone PSA and PSAD correlated with PIRADS score in the detection of csPCa using MRI-US fusion prostate biopsy.</p> Methods <p>Men with PSA of 4–10 who underwent prostate multiparametric MRI of the prostate (mpMRI) were divided into two groups (4—&lt; 7 and ≥ 7–10&#xa0;ng/mL) and according to PSA density (&lt; 0.10, 0.10–0.20 and &gt; 0.20). Subgroups according to PIRADS score were made for each group. Chi-square test was utilized for analysing the comparison of histopathology results between the PSA and PSA density subgroups per PIRADS lesion category. Using receiver-operating characteristic (ROC) curves, the diagnostic accuracy of PSA and PSAD in identifying csPCa were evaluated, and the best cutoff values were identified.</p> Results <p>Overall detection rate of csPCa was 40.4% (146/361) in the cohort of men with gray zone PSA value. Clinically significant difference in csPCa detection rate was observed in the PSAD subgroups (<i>p</i> =  &lt; 0.001) while no significant difference was observed in the two groups of PSA (<i>p</i> = 0.387). On subgroup analysis, only the PSAD subcategories of PIRADS 4 and 5 showed significant difference (<i>p</i> = 0.028 and <i>p</i> = 0.003, respectively). Based on the ROC curve, the optimal cutoff for PSA was 6.32 with sensitivity and specificity of 65.1% and 43.3%, respectively [AUC 0.54 (0.48—0.60)]. PSAD optimal cutoff was 0.139 with sensitivity and specificity of 80.8% and 49.3%, respectively [AUC 0.67 (0.61—0.72)].</p> Conclusions <p>PSA and PSAD combined with PIRADS v2.1 provide more diagnostic value than when used alone and can be used to counsel men who will undergo MRI-US fusion biopsy. In the gray zone, PSAD is a more reliable diagnostic predictor of csPCa than PSA.</p>