Previous reports have focused on cardiovascular and bleeding events in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, antithrombotic treatment strategies and clinical outcomes after second-generation drug-eluting stents (DES) implantation in AF patients remain to be determined. We enrolled 244 consecutive AF patients treated with second-generation DES. The study population was derived from multi-center AF registry (including 8 centers in Japan) from 2010 to 2012. Prescription of antithrombotic agents and clinical outcomes were retrospectively examined. Ninety-two patients (37.7%) were prescribed dual antiplatelet therapy (DAPT) at discharge and 152 patients (62.3%) were given DAPT plus oral anticoagulation (OAC) with warfarin. The median follow-up period was 730 days. Kaplan-Meier analysis showed that major adverse cardiac and cerebrovascular events (MACCE) were not significantly different (2-year event rate, 17.6 vs. 13.5%, p = 0.37), but bleeding events were significantly higher in the DAPT plus OAC group than in the DAPT group (2-year event rate, 6.1 vs. 17.9%, p = 0.033). In a sub-analysis of DAPT plus OAC patients, adequate time in the therapeutic range (TTR) group (TTR ≥ 65%) was not significantly different from the suboptimal OAC group (TTR < 65%) for bleeding events, but it had a lower incidence of MACCE, resulting in better net clinical outcomes (composite of MACCE and major bleeding, 2-year event rate, 9.2 vs. 27.8%, p = 0.008). DAPT plus OAC remains more common in AF patients undergoing PCI with second-generation DES. Under adequate TTR, DAPT plus OAC showed better net clinical outcomes by reducing MACCE without increasing bleeding.