Triflusal is a derivative of acetylsalicylic acid but it exhibits different pharmacological and pharmacokinetic properties. The object of this study was to evaluate the efficacy of additional use of triflusal in patients who underwent drug-eluting stent implantation. First, we prospectively tested platelet function with a rapid platelet function analyzer (VerifyNow-Aspirin) in patients with stable angina (male, age, 61.6 +/- 8.3, body weight, 69.3 +/- 11.2 kg) who maintained dual (aspirin 100 mg and clopidogrel 75 mg per day, n = 23) or triple (aspirin 100 mg, clopidogrel 75 mg, and triflusal 300 mg per day, n = 23) therapy for more than one month. They were randomly assigned to a group. The triple group showed superior inhibition of arachidonic acid induced platelet aggregation compared to the dual group (420.2 +/- 47.7 ARU versus 465.0 +/- 71.2 ARU, P = 0.016). Second, we compared composite outcomes (death, myocardial infarction, and nonhemorrhagic stroke) after drug-eluting stent (DES) implantation between the dual (n = 1474) and triple (n = 433) groups in the prospective Seoul National University Hospital drug-eluting stent (SNUH-DES) cohort. The triple group had more current smokers, male patients, and patients with a previous history of revascularization. Also, the triple group underwent more complex interventions such as left main, chronic total occlusion, long lesion, and restenotic lesion than the dual group. In spite of their higher risk profiles, the triple group patients showed comparable composite outcomes (19 cases, 4.4%) to those of the dual group ones (41 cases, 2.8%) (P = 0.12). The triflusal-based triple antiplatelet therapy achieved superior platelet inhibition compared to the dual therapy ex vivo and it could be applied after complex intervention with DES.