Background The factors influencing three major outcomes-death, stroke/systemic embolism (SE), and major bleeding-have not been investigated in a large international cohort of unselected patients with newly diagnosed atrial fibrillation (AF). Methods and results In 28,628 patients prospectively enrolled in the GARFIELD-AF registry with 2-year followup, we aimed at analysing: (1) the variables influencing outcomes; (2) the extent of implementation of guideline-recommended therapies in comorbidities that strongly affect outcomes. Median (IQR) age was 71.0 (63.0 to 78.0) years, 44.4% of patients were female, median (IQR) CHA2DS2-VASc score was 3.0 (2.0 to 4.0); 63.3% of patients were on anticoagulants (ACs) with or without antiplatelet (AP) therapy, 24.5% AP monotherapy, and 12.2% no antithrombotic therapy. At 2 years, rates (95% CI) of death, stroke/SE, and major bleeding were 3.84 (3.68; 4.02), 1.27 (1.18; 1.38), and 0.71 (0.64; 0.79) per 100 personyears. Age, history of stroke/SE, vascular disease (VascD), and chronic kidney disease (CKD) were associated with the risks of all three outcomes. Congestive heart failure (CHF) was associated with the risks of death and stroke/SE. Smoking, non-paroxysmal forms of AF, and history of bleeding were associated with the risk of death, female sex and heavy drinking with the risk of stroke/SE. Asian race was associated with lower risks of death and major bleeding versus other races. AC treatment was associated with 30% and 28% lower risks of death and stroke/SE, respectively, compared with no AC treatment. Rates of prescription of guideline-recommended drugs were suboptimal in patients with CHF, VascD, or CKD. Conclusions Our data show that several variables are associated with the risk of one or more outcomes, in terms of death, stroke/SE, and major bleeding. Comprehensive management of AF should encompass, besides anticoagulation, improved implementation of guideline-recommended therapies for comorbidities strongly associated with outcomes, namely CHF, VascD, and CKD.