Background: In patients with acute coronary syndrome (ACS) with a high risk of ischemia, the impact of ticagrelor monotherapy after short-term dual antiplatelet therapy (DAPT) has not been clearly elucidated. Methods: This post hoc analysis of the TICO trial (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome) compared the impact of ticagrelor monotherapy after 3-month DAPT versus ticagrelor-based 12-month DAPT in patients with high-ischemic risk ACS, defined as any of the following: number of stents implanted ≥3, total stent length >60 mm, complex procedures (chronic total occlusion, left main occlusion, or bifurcation plaques remedied using the 2-stent technique), or a history of diabetes or chronic kidney disease. Ischemic (composite of death, myocardial infarction, stent thrombosis, stroke, and target vessel revascularization) and bleeding outcomes (major bleeding) were evaluated at 12 months. Results: Of the total population (N=3056), 1473 (48.2%) patients were identified as having high-ischemic risk ACS. The rate of the ischemic outcome was significantly higher in high-ischemic risk ACS patients than in nonhigh-ischemic risk ACS patients (3.9% versus 1.9%, hazard ratio, 2.14 [95% CI, 1.37–3.35], P =0.001). Furthermore, the risk of major bleeding (3.2% versus 1.5%, hazard ratio, 2.23 [95% CI, 1.36–3.68], P =0.001) and the composite ischemic and bleeding outcome (6.6% versus 3.3%, hazard ratio, 2.02 [95% CI, 1.44–2.84], P <0.001) were also higher in the high-risk ACS population. In ACS patients with or without high-ischemic risk, the effect of ticagrelor monotherapy after 3-month DAPT, as compared to that of 12-month DAPT, was consistent with ischemic ( P _int =0.718), bleeding ( P _int =0.092), and composite outcomes ( P _int =0.094) without significant interactions. Conclusions: There were no significant heterogeneities in the impact of ticagrelor monotherapy after 3-month DAPT compared with that of ticagrelor-based 12-month DAPT on clinical outcomes according to the presence of high-ischemic risk. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02494895.