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AIMS: Coronary artery disease (CAD) polygenic risk scores (PRS) enhance risk stratification, but it is unknown whether the degree varies across the spectrum of atherosclerotic cardiovascular disease (ASCVD). We compared the association of a CAD PRS and coronary events in patients with ASCVD and a prior ischemic event, ASCVD without event, and without overt ASCVD.METHODS: Genotyped patients from 6 multinational cardiovascular trials were categorized into low (bottom 20%), intermediate (middle 60%), and high (top 20%) genetic risk using a genome-wide CAD PRS, then grouped by ASCVD status. The primary endpoint was any major coronary event, a composite of death from coronary disease, myocardial infarction, or coronary revascularization.RESULTS: 59,905 participants (mean age, 66 years; 71% male) were included; 47,456 (79%) had established ASCVD. Compared with low genetic risk, major coronary events were more frequent in high (HR, 2.06; 95%CI, 1.88-2.24; p<0.001) and intermediate (HR, 1.57; 95%CI, 1.45-1.70; p<0.001) genetic risk. Genetic risk was more strongly associated with major coronary events in patients without overt ASCVD (HR between high vs. low genetic risk, 4.63) than patients with ASCVD without (HR, 1.73) or with an ischemic event (HR, 1.63) (Pinteraction<0.001). Absolute risk difference between high and low genetic risk was comparable across ASCVD categories (5.0-7.0% difference at 3 years).CONCLUSION: A CAD PRS was associated with incident major coronary events in all ASCVD categories. Although genetics provided the strongest relative association in patients without established ASCVD, the absolute risk gradient was comparable for patients with and without ASCVD.