Purpose/objective(s) To assess subcutaneous adipose tissue characteristics by computed tomography (CT) as potential imaging biomarkers predictive of biochemical recurrence in men with high-risk prostate cancer receiving radiotherapy (RT). Materials and methods This retrospective study included men with high-risk prostate cancer (PSA>20 ng/ml, Gleason score ≥8, or clinical extraprostatic extension) treated between 2001 and 2012. All patients received definitive, dose-escalated external beam RT along with a course of neoadjuvant, concurrent, and adjuvant androgen deprivation therapy (ADT). Each patient also had a treatment planning CT that included the L4-L5 vertebral interface and prostate specific antigen (PSA) measurements for at least 2 years following RT. The subcutaneous adipose tissue was contoured on a single axial CT slice at the level of L4-L5. The average CT attenuation, in Hounsfield units (HU), of the structure was calculated and defined as SATHU. SATAREA was defined as the cross-sectional area of the structure (in cm2) that was then normalized by the square of patient height. Biochemical failure (BF) was defined as a PSA rise of 2 ng/ml from the nadir. Freedom from BF (FFBF) was calculated from start time of ADT using the Kaplan-Meier method. Estimates of FFBF were stratified by SATHU and SATAREA quartiles. Results A total of 171 men met the inclusion criteria with a median follow-up of 5.6 years. The mean SATHU (±standard deviation) was −99.2 HU (±6.1 HU), and the mean SATAREA was 93.2 cm2/m2 (±39.4 cm2/m2). The 5- and 8-year rates of FFBF across all patients were 81.5% and 73.5%, respectively. Patients in the lowest quartile of SATHU experienced significantly higher FFBF compared to the other quartiles (Q4 vs. Q1, P = 0.017; Q4 vs. Q2, P = 0.045; Q4 vs. Q3, P = 0.044). No other differences in FFBF were observed between quartiles of SATAREA or other quartiles of SATHU. Conclusion Lower subcutaneous adipose tissue density was associated with a lower rate of BF following RT with ADT for men with high-risk prostate cancer. Further research is needed to elucidate the biological underpinnings of this clinical finding and the role adipose tissue plays in modulating oncologic behavior and outcomes.