Abstract Background  Clinical complexity is common in atrial fibrillation (AF) patients. We assessed the impact of clinical complexity on oral anticoagulant (OAC) treatment patterns and major adverse outcomes in a contemporary cohort of AF patients. Methods  The GLORIA-AF Phase II and III Registry enrolled newly diagnosed AF patients with at least one stroke risk factor. Among patients with CHA 2 DS 2 -VASc score ≥2, we defined four domains of perceived clinical complexity: frail elderly (age ≥75 years and body mass index <23 kg/m 2 ), chronic kidney disease (CKD, creatinine clearance <60 mL/min), history of bleeding, and those with ≥2 of the above conditions. We evaluated the associations between clinical complexity domains and antithrombotic treatment prescription, risk of OAC discontinuation, and major adverse outcomes. Results  Among the 29,625 patients included (mean age 69.6 ± 10.7 years, 44.2% females), 9,504 (32.1%) presented with at least one complexity criterion. Clinical complexity was associated with lower OAC prescription, with stronger associations in frail elderly (odds ratio OR: 0.47, 95% confidence interval CI: 0.36–0.62) and those with ≥2 complexity domains (OR: 0.50, 95% CI: 0.44–0.57). Risk of OAC discontinuation was higher among frail elderly (hazard ratio HR: 1.30, 95% CI: 1.00–1.69), CKD (HR: 1.10, 95% CI: 1.02–1.20), and those with ≥2 complexity domains (HR: 1.39, 95% CI: 1.23–1.57). Clinical complexity was associated with higher risk of the primary outcome of all-cause death, thromboembolism, and major bleeding, with the highest magnitude in those with ≥2 criteria (HR: 1.63, 95% CI: 1.43–1.86). Conclusion  In AF patients, clinical complexity influences OAC treatment management, and increases the risk of poor clinical outcomes. These patients require additional efforts, such as integrated care approach, to improve their management and prognosis.