Few genetic risk factors have been demonstrated to be specifically associated with aggressive prostate cancer (PrCa). Here, we report a case-case study of PrCa comparing the prevalence of germline pathogenic/likely pathogenic (P/LP) genetic variants in 787 men with aggressive disease and 769 with non-aggressive disease. Overall, we observed P/LP variants in 11.4% of men with aggressive PrCa and 9.8% of men with non-aggressive PrCa (two-tailed Fisher’s exact tests, P = 0.28). The proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive PrCa exceeded that observed in men with non-aggressive PrCa; 18/787 carriers (2.3%) and 4/769 carriers (0.5%), P = 0.004, and 14/787 carriers (0.02%) and 5/769 carriers (0.01%), P = 0.06, respectively. Our findings contribute to the extensive international effort to interpret the genetic variation identified in genes included on gene-panel tests, for which there is currently an insufficient evidence-base for clinical translation in the context of PrCa risk.This article is protected by copyright. All rights reserved.