Objective To evaluate whether baseline prostate atrophy (PA) extent is associated with prostate cancer (PCa) incidence at 2-year repeat prostate biopsy in a clinical trial with systematic biopsies. Materials and Methods We performed a retrospective analysis of 3165 men 50-75 years old with prostate-specific antigen between 2.5 and 10 ng/mL and a prior negative biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events trial who underwent a 2-year repeat biopsy. PA extent was defined as the percentage of cores with atrophic changes. The association of baseline PA with positive 2-year biopsies was evaluated with logistic regression in uni- and multivariable analysis, controlling for baseline covariates. Results PA involving none, 1%-25%, 26%-50%, 51%-75%, and >75% of the baseline cores was observed in 966 of 3165 (30.5%), 1189 of 3165 (37.6%), 677 of 3165 (21.4%), 209 of 3165(6.6%), and 124 of 3165 (3.9%) cases, respectively. More extensive PA was associated with older age, lower prostate-specific antigen, larger prostate volume, and higher prevalence of acute and chronic inflammations (all P < .05). Compared to subjects without PA, those with 1%-25%, 26%-50%, 51%-75%, and >75% core involvement had an odds ratio for PCa of 0.65 (95% confidence interval [CI] = 0.52-0.81), 0.60 (95% CI = 0.46-0.78), 0.56 (95% CI = 0.37-0.86), and 0.35 (95% CI = 0.19-0.67), respectively. In multivariable analysis, the extent of PA was independently associated with lower PCa risk (P < .001). More extensive PA was associated with lower incidence of low-grade (Gleason 2-6) and high-grade (Gleason 7-10) PCa. Conclusion The extent of baseline PA is independently associated with lower PCa risk in a dose-dependent fashion.