Our study provides evidence that aspirin specifically benefits older individuals with elevated lipoprotein(a) [Lp(a)] genotypes in the setting of primary prevention of cardiovascular disease (CVD). In 12,815 genotyped participants in the ASPREE (ASPirin in Reducing Events in the Elderly) trial, aspirin reduced major adverse cardiovascular events (MACE) by 1.7 events per 1,000 person-years and increased clinically significant bleeding (BLEEDS) by 1.7 events per 1,000 person-years (indicating no net benefit of aspirin). However, in the rs3798220-C carrier group and the highest quintile of a lipoprotein(a) genomic risk score (LPA-GRS) distribution, aspirin reduced MACE by 11.4 and 3.3 events, respectively, without significantly increased bleeding risk, indicating a shift toward the net benefit of aspirin.