The Comparison of Bioactive-Stent to the Everolimus-Eluting Stent in Acute Coronary Syndrome (BASE-ACS) trial demonstrated an outcome of titanium-nitride-oxide-coated bioactive stents (BAS) non-inferior to everolimus-eluting stents (EES) in patients presenting with acute coronary syndrome (ACS). We performed a post hoc analysis of the BASE-ACS trial in patients with, versus those without, preexisting vascular disease. We randomized 827 patients (1:1) presenting with ACS to receive either BAS or EES. The primary end point was major adverse cardiac events (MACE): a composite of cardiac death, non-fatal myocardial infarction (MI), or ischemia-driven target lesion revascularization (TLR). A total of 169 (20.4%) patients had preexisting vascular disease. Median follow-up was 5.0 years. The incidence of MACE was higher in patients with, versus those without, preexisting vascular disease (22.5% vs 13.5%, respectively, P = .004). This was driven by more frequent cardiac death and non-fatal MI (5.9% vs 2.4% and 11.8% vs 5.5%, P = .02 and P = .003, respectively). The rates of ischemia-driven TLR were comparable (P > .05). All events were comparable between the 2 matched-pair subgroups (P > .05 for all). In patients treated with early percutaneous coronary intervention for ACS, the long-term outcome was worse in patients with, versus those without, preexisting vascular disease.