Background This study was designed to investigate the efficacy of the selective 5-HT2A receptor antagonist sarpogrelate on the prevention of in-stent neointimal hyperplasia in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Methods This prospective, randomized study compared sarpogrelate group (n=56, aspirin plus clopidogrel plus sarpogrelate) and control group (n=54, aspirin plus clopidogrel) for 9 months in patients undergoing PCI. All patients received only paclitaxel-eluting stent. The primary endpoints were late loss as assessed by quantitative coronary angiography and in-stent restenosis (ISR) at 9 months follow-up. Secondary endpoints were cardiac death, non-fatal myocardial infarction, and target lesion revascularization (TLR). Results There were no significant differences in the baseline and angiographic data between the 2 groups. At 9 months follow-up, mean in-stent late loss was 0.41 mm in the sarpogrelate group (n=49) and 0.55 mm in the control group (n=48) (p=0.148). The rate of in-stent restenosis was 8.2% in sarpogrelate group and 14.6% in control group (p=0.319). Conclusion These data suggest that triple antiplatelet therapy including sarpogrelate is safe but did not show more effectiveness at preventing in-stent neointimal hyperplasia than a dual antiplatelet regimen in patients underwent PCI with DES.