Abstract Objectives To investigate the impact of ticagrelor monotherapy following one-month dual antiplatelet therapy (DAPT) on clinical outcomes after percutaneous coronary intervention (PCI) in patients with established cardiovascular disease (CVD) who were enrolled in the Global Leaders Trial. Background The impact of prolonged monotherapy with P2Y12 inhibitors after PCI in patients with CVD is undetermined. Methods GLOBAL LEADERS was a randomized, superiority, all-comers trial comparing one-month DAPT with ticagrelor and aspirin followed by 23-month ticagrelor monotherapy (experimental treatment) with standard 12-month DAPT followed by 12-month aspirin monotherapy (reference treatment) in patients treated with a biolimus A9-eluting stent. The cohort was stratified according to those with- and without established CVD, defined as a history of ≥1 prior myocardial infarction (MI), PCI, coronary artery bypass operation, stroke or peripheral vascular disease. The degree of CVD was defined according to the number of vascular territories effected (1, 2, ≥3). The primary endpoint was a composite of all-cause death or new Q-wave MI at 2-years. Secondary endpoints were the patient orientated composite endpoint (POCE) of death, stroke, MI and any revascularization; definite stent thrombosis and net adverse cardiovascular events a composite of POCE and BARC 3 or 5 bleeding. Results Amongst the 15,761 patients included in this cohort were 6693 patients (42.5%) with- and 9068 patients without established CVD. Patients with CVD were older, and had significantly higher rates of diabetes, hypertension, and hypercholesterolaemia (P<0.01). The incidence of the primary endpoint was significantly higher in patients with established CVD (5.1% vs. 3.3%, P<0.001) as were all secondary endpoints and their individual components. There was a trend for a reduction in the primary endpoint in patients with established CVD receiving the experimental treatment (4.6% vs. 5.6%, HR0.82 [0.66–1.02], p=0.07), which was not seen in those without prior CVD (3.2% vs. 3.3%, HR 0.95 [0.76–1.19, p=0.66; p(interaction)=0.37). Compared with patients without CVD the incidence of the primary and second endpoints and all their individual components, other than BARC 3/5 bleeding, rose significantly with an increasing degree of CVD. In an unadjusted model, compared with patients without CVD, the hazard ratio for the primary endpoint rose from 1.5 (1.21–1.81) to 3.0 (2.32–4.00) in patients with one and three territories of CVD, respectively. Similar rises were seen in models adjusted by age (1.3 [1.01–1.60] to 2.56 [1.94–3.38]) and age, left ventricular ejection fraction, clinical presentation and anti-platelet strategy (1.4 [1.10–1.68] to 2.26 [1.69–3.02]). Conclusions PCI outcomes are poorer in patients with increasing degrees of CVD compared to those without. Prolonged monotherapy with ticagrelor does not mitigate this risk suggesting a greater need to focus on modifiable risk factors