Objective. To evaluate the role of prostate-specific antigen density (PSAD) in different Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1) categories to avoid an unnecessary biopsy in transition zone (TZ) patients with PSA ranging from 4 to 20 ng/mL. Materials and Methods. In this retrospective and single-center study, 333 biopsy-naïve patients with TZ lesions who underwent biparametric magnetic resonance imaging (bp-MRI) were analyzed from January 2016 to March 2020. Multivariate logistic regression analyses were performed to determine independent predictors of clinically significant prostate cancer (cs-PCa). The receiver operating characteristic (ROC) curve was used to compare diagnostic performance. Results. PI-RADS v2.1 and PSAD were the independent predictors for TZ cs-PCa in patients with PSA 4-20 ng/mL. 0.9% (2/213), 10.0% (7/70), and 48.0% (24/50) of PI-RADS v2.1 score 1-2, 3, and 4-5 had TZ cs-PCa. However, for patients with PI-RADS v2.1 score 1-2, there were no obvious changes in the detection of TZ cs-PCa (0.8% (1/129), 1.3% (1/75), and 0.0% (0/9)) combining with different PSAD stratification (
PSAD
<
0.15
, 0.15-0.29, and ≥0.30 ng/mL/mL). For patients with PI-RADS v2.1
score
≥
3
, the TZ cs-PCa detection rate significantly varied according to different PSAD stratification. A PI-RADS v2.1 score 3 and
PSAD
<
0.15
and 0.15-0.29 ng/mL/mL had 8.6% (3/35) and 3.7% (1/27) of TZ cs-PCa, while a PI-RADS v2.1 score 3 and
PSAD
≥
0.30
ng
/
mL
/
mL
had a higher TZ cs-PCa detection rate (37.5% (3/8)). A PI-RADS v2.1 score 4-5 and PSAD <0.15 ng/mL/mL had no cs-PCa (0.0% (0/9)). In contrast, a PI-RADS v2.1 score 4-5 and PSAD 0.15-0.29 and ≥0.30 ng/mL/mL had the highest cs-PCa detection rate (50.0% (10/20), 66.7% (14/21)). It showed the highest AUC in the combination of PI-RADS v2.1 and PSAD (0.910), which was significantly higher than PI-RADS v2.1 (0.889,
P
=
0.039
) or PSAD (0.803,
P
<
0.001
). Conclusions. For TZ patients with PSA 4-20 ng/mL, PI-RADS v2.1
score
≤
2
can avoid an unnecessary biopsy regardless of PSAD. PI-RADS v2.1
score
≥
3
may avoid an unnecessary biopsy after combining with PSAD. PI-RADS v2.1 combined with PSAD could significantly improve diagnostic performance.