Background: The benefit of aspirin among patients with stable atherosclerosis without a prior ischemic event is not well defined.Hypothesis: Aspirin would be of benefit in outpatients with atherosclerosis with prior ischemic events, but not in those without ischemic events.Methods: Subjects from the Reduction of Atherothrombosis for Continued Health registry were divided according to prior ischemic event (n = 21 724) vs stable atherosclerosis, but no prior ischemic event (n = 11 872). Analyses were propensity score matched. Aspirin use was updated at each clinic visit and considered as a time-varying covariate. The primary outcome was the first occurrence of cardiovascular death, myocardial infarction, or stroke.Results: In the group with a prior ischemic event, aspirin use was associated with a marginally lower risk of the primary outcome at a median of 41 months (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.65-1.01, P = 0.06). In the group without a prior ischemic event, aspirin use was not associated with a lower risk of the primary outcome at a median of 36 months (HR: 1.03, 95% CI: 0.73-1.45, P = 0.86).Conclusions: In this observational analysis of outpatients with stable atherosclerosis, aspirin was marginally beneficial among patients with a prior ischemic event; however, there was no apparent benefit among those with no prior ischemic event.