SummaryThere is increasing interest in periprostatic fat and its influence on prostate cancer aggressiveness. In vitro data suggest that adipose stromal/stem cells (ASCs) can increase production of cytokines and growth factors resulting in invasive growth and metastasis in prostate cancer. The objective of the study was to determine the interaction between 5α‐reductase inhibitors (5ARIs) and periprostatic adipose tissue (PPAT) and factors of prostate cancer aggressiveness. In this retrospective study, we identified 61 patients treated with 5ARIs for a period of ≥12 months before undergoing radiation therapy (brachytherapy or external beam radiotherapy). The control group consisted of 117 patients without any exposure to 5ARIs. Prior to being treated, all patients underwent abdominal computed tomography (CT). To measure PPAT, we defined the fat pad anteriorly to the prostate, as well as the intra‐abdominal visceral adipose tissue (VAT) and subcutaneous tissue (SAT) at the level of L4/L5. All contours were performed manually. These adipose tissue measurements were correlated with the Cancer of the Prostate Risk Assessment (CAPRA) score using Pearson correlation coefficient. Differences in fat contents were evaluated using Student's t‐test. Median time on 5ARIs for the 61 patients was 12 months (range 12–96). Patient on 5ARIs had a significantly (p < 0.001) smaller PPAT (0.4, SD 0.5) than patients without a 5ARI (0.6 cc, SD 0.4). There was no significant correlation between the CAPRA score and fat measurements when adjusted for 5ARI use (p = 0.18). In non‐5ARI users, BMI was not correlated with PPAT but was correlated with SAT and VAT volume and its density. There were no significant differences in diabetics (p = 0.3), metformin users (p = 0.4) or statin users (p = 0.09) between both groups. 5ARIs taken for at least 12 months induce changes in PPAT volume. Whether these changes or the extent of changes will have an influence on outcome remains unknown.