Abstract Objectives This study sought to investigate the incidence, management, and clinical relevance of atrial fibrillation (AF) during and after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and evaluate outcomes of different antithrombotic strategies. Background Uncertainty exists regarding the optimal antithrombotic strategy in patients with AF who are undergoing PCI with DES. Methods Using a consecutive series of 10,027 patients who underwent DES implantation between 2003 and 2011, we evaluated the overall prevalence and clinical impact of AF. In addition, we compared the efficacy and safety of dual antiplatelet therapy (DAPT) (aspirin plus clopidogrel) and triple therapy (DAPT plus warfarin) among patients with AF. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke. Results Overall, 711 (7.1%) patients had a diagnosis of AF at the index PCI. Patients with AF were older, had more comorbid conditions, and more often had a history of strokes; most patients with AF (88.4%) received DAPT rather than triple therapy (10.5%) at discharge. The rate of primary outcome after PCI during the 6-year follow-up period was significantly higher in patients with AF than in those without AF (22.1% vs. 8.0%; p < 0.001). This trend was consistent for major bleeding (4.5% vs. 1.5%; p < 0.001). After multivariable adjustment, the presence of AF was significantly associated with a higher risk of primary outcome (hazard ratio HR: 2.33; 95% confidence interval CI: 1.95 to 2.79; p < 0.001) and major bleeding (HR: 2.01; 95% CI: 1.32 to 3.06; p = 0.001). Among patients with AF, adjusted risk for the primary outcome was similar between the DAPT group and the triple therapy group (HR: 1.01; 95% CI: 0.60 to 1.69; p = 0.98), but triple therapy was associated with a significantly higher risk of hemorrhagic stroke (HR: 7.73; 95% CI: 2.14 to 27.91; p = 0.002) and major bleeding (HR: 4.48; 95% CI: 1.81 to 11.08; p = 0.001). Conclusions Among patients receiving DES implantation, AF was not rare and was associated with increased ischemic and bleeding risk. In patients with AF, triple therapy was not associated with decreased ischemic events but was associated with increased bleeding risk compared to DAPT.