This study compared the risk of mortality in atrial fibrillation (AF) patients treated adherent to the 2012 European Society of Cardiology (ESC) guidelines for stroke prevention and those who were not treated according to guideline recommendations. This study used the Taiwan National Health Insurance Research Database. From 1996 to 2011, 354,649 newly diagnosed AF patients were identified as the study population. Among the study cohort, 45,595 and 309,054 patients were defined as Guideline-Adherent and Non-Adherent groups, respectively. During the follow up of 1,480,280 person-years, 133,552 (37.7%) patients experienced mortality. The risk of mortality was lower among AF patients whose treatment was adherent to the guideline recommendation for stroke prevention than those whose treatment was not (annual risk of mortality = 4.3% versus 10.0%) with an adjusted hazard ratio of 0.62 (95% confidence interval = 0.61-0.64, p value < 0.001) after adjusting for age, gender, CHA2DS2-VASc score and antiplatelet therapy. The findings were consistently observed after propensity matching analysis. In conclusion, the risk of mortality was lower for AF patients who were treated according to the antithrombotic recommendations of the 2012 ESC guidelines, guided by the CHA2DS2-VASc score. Better efforts to implement guidelines would lead to improved outcomes for patients with AF.