<p>Multimorbidity, frailty, and polypharmacy are associated with worse outcomes in patients with atrial fibrillation (AF), leading to ‘clinically complex’ patient phenotypes. Possible differences between European and Asian patients regarding these aspects have not been studied.&#xa0;We studied AF patients derived from two large prospective observational AF registries, conducted in Europe and Asia. Multimorbidity and polypharmacy were defined according to the number of comorbidities and drugs at baseline. Frailty was defined according to a 40-items frailty index (FI). Prescription of OAC was assessed at baseline. The primary outcome was the composite of all-cause death and major adverse cardiovascular events.&#xa0;European patients had a higher burden of multimorbidity, frailty, and polypharmacy domains compared with Asians. Asian patients with these domains were less likely to be prescribed OAC than Europeans, especially those who were frail. After adjustments, being frail was associated with lower OAC prescription, with Asians less likely prescribed than Europeans (OR 0.34, 95% CI 0.25–0.45 vs. OR 0.47, 95% CI 0.40–0.55, p_int = 0.037). Adjusted Cox regression found that multimorbidity, frailty, and polypharmacy domains were associated with a higher risk of the composite outcome. On subgroup analysis, frail Asian patients had a higher risk of the composite outcome (p_int = 0.007) than Europeans.&#xa0;Multimorbidity, frailty and polypharmacy have different epidemiological characteristics amongst European and Asian AF patients. Being frail was associated with a higher likelihood of not being prescribed OAC, particularly in Asian patients. The adverse impact of ‘clinically complex’ patient phenotypes on risks of adverse outcomes was greater in Asian patients than in Europeans.</p> Graphical Abstract <p></p>