BACKGROUND: In two large randomized controlled trials, 5α-reductase inhibitors (5-ARIs) were shown to prevent prostate cancer. No prior work had shown the effect of 5-ARIs on those already diagnosed with low-risk prostate cancer. OBJECTIVE: Our aim was to determine the effect of 5-ARIs on pathologic progression in men on active surveillance. DESIGN, SETTING, AND PARTICIPANTS: We conducted a single-institution retrospective cohort study comparing men taking a 5-ARI versus no 5-ARI while on active surveillance for prostate cancer. MEASUREMENTS: Pathologic progression was evaluated and defined as Gleason score >6, maximum core involvement >50%, or more than three cores positive on a follow-up prostate biopsy. Kaplan-Meier analyses were conducted along with multivariable Cox proportional hazard regression modeling for predictors of pathologic progression. RESULTS AND LIMITATIONS: A total of 288 men on active surveillance met the inclusion criteria. The median follow-up was 38.5 mo (interquartile range: 23.6-59.4) with 93 men (32%) experiencing pathologic progression and 96 men (33%) abandoning active surveillance. Men taking a 5-ARI experienced a lower rate of pathologic progression (18.6% vs 36.7%; p=0.004) and were less likely to abandon active surveillance (20% vs 37.6%; p=0.006). On multivariable Cox proportional hazards analysis, lack of 5-ARI use was most strongly associated with pathologic progression (hazard ratio: 2.91; 95% confidence interval, 1.5-5.6). The main study limitation was the retrospective design and variable duration of 5-ARI therapy. CONCLUSIONS: The 5-ARIs were associated with a significantly lower rate of pathologic progression and abandonment of active surveillance.