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Introduction Obesity is associated with poor prostate cancer-specific outcomes. Body mass index, a commonly used surrogate of obesity, does not adequately describe fat distribution, which can instead be assessed using medical imaging. Abdominal visceral obesity, a better indicator of metabolic health, has been associated with increased prostate cancer risk. Similarly, periprostatic adipose tissue (PPAT), a type of visceral fat in close proximity to the prostate has a postulated role in prostate cancer aggressiveness. We hypothesised that elevated quantities of visceral fat, both abdominal and periprostatic would be associated with increased disease aggressiveness. To gain insight into potential contributing mechanisms, we examined gene expression pathways differentially expressed in association with adiposity measures. Methods Abdominal adipose tissue, both subcutaneous and visceral (n=244), and PPAT (n=309) were quantified from the radiation planning computed tomography (CT) scans from prostate cancer patients treated with radiotherapy and ADT in the Northern Ireland Cancer Centre between 2005-2009. Abdominal fat was measured at L4/L5 and PPAT at the midpoint of pubic symphysis using a threshold of -190 to -30 Hounsfield Units to identify fat. Associations of adipose tissue quantity, categorised using tertiles of fat quantity, with Gleason score (≥4+3 versus ≤3+4) were assessed using univariable and multivariable logistic regression analysis. Associations between adipose tissue quantity and risk of biochemical recurrence and metastasis were examined using Cox regression. In a subset of patients with tumour biopsy transcriptomic data (n=183), an exploratory Gene Set Enrichment Analysis (GSEA) was performed to identify enriched gene pathways in the tumours of those with high versus low fat measures, defined using the median fat quantity. Results High PPAT was significantly associated with increased risk of high grade prostate cancer (Tertile 3 vs. Tertile 1; age adjusted OR 2.05; 95%CI 1.17-3.62; p=0.01). There was a trend for increased risk of high grade disease in those with high abdominal subcutaneous (T3 vs. T1; age adjusted OR 1.73; 95%CI 0.92-3.30) and visceral (T3 vs. T1; age adjusted OR 1.21; 95%CI 0.66-2.25) fat measures but this was not significant. In GSEA, those with high PPAT showed enrichment of the KEGG adipocytokine signalling pathway (nominal p-value=0.004) whilst those with high subcutaneous fat had enrichment of pathways involved in lipid and cholesterol metabolism. No adipose tissue measure was significantly associated with prostate cancer-specific outcomes following a median follow up of 10.1 years. Conclusions Elevated quantities of PPAT are associated with increased risk of high grade prostate cancer and enriched tumour adipocytokine signalling, suggesting a possible paracrine role of PPAT in prostate cancer aggressiveness. This is the first study to explore potential mechanisms of PPAT using tumour gene expression data. If confirmed, this may in part explain the link between obesity and aggressive prostate cancer. Citation Format: Sarah J. Winter, Suneil Jain, Gillian Prue, Conor K. McGarry, Alan R. Hounsell, Michelle Leech, Emma H. Allott. Elevated periprostatic fat is associated with high grade prostate cancer in radiotherapy-treated patients [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A025.