BACKGROUND: Evidence for non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy for older patients with atrial fibrillation (AF) and drug-eluting stents is lacking. OBJECTIVES: We aimed to evaluate the safety and efficacy of NOAC monotherapy in older AF patients with drug-eluting stents. METHODS: This is a secondary analysis of the ADAPT AF-DES randomised trial comparing NOAC monotherapy with combination therapy with NOAC plus clopidogrel in patients with AF and drug-eluting stents. Patients were stratified by age (≥75 years and <75 years). Apixaban or rivaroxaban was used as the NOAC. The primary endpoint was a net adverse clinical event at 1 year after randomisation, defined as a composite of all-cause death, myocardial infarction, stent thrombosis, stroke, systemic embolism or major or clinically relevant non-major bleeding defined by the International Society on Thrombosis and Haemostasis criteria. RESULTS: Among 960 patients included in the ADAPT AF-DES trial, 376 (39.2%) patients were aged ≥75 years. In patients aged ≥75 years, the incidence of the primary endpoint was lower in the NOAC monotherapy group (9.8% vs. 22.3%; adjusted hazard ratio, 0.37; 95% confidence interval, 0.21-0.66; P < .001) than in the combination therapy group. In contrast, the incidences did not differ between treatment strategies in patients aged <75 years. The interaction between age groups and strategy groups did not reach statistical significance (P for interaction = .095). The reduction in major or clinically relevant non-major bleeding with NOAC monotherapy was consistent across age groups. In contrast, the benefit of NOAC monotherapy in major adverse cardiac and cerebrovascular events was more pronounced in patients aged ≥75 years, with a statistically significant interaction. CONCLUSIONS: In this post hoc analysis, NOAC monotherapy was associated with a lower risk of net adverse clinical events, specifically within the older age subgroup. Tailored approach regarding age and individual ischaemic risk may be needed.