Background XS0601, consisting of active ingredients (Chuangxiongol and paeoniflorin), has been shown to inhibit arterial neointimal hyperplasia in animal models and in preliminary human studies. The objective of this study was to evaluate the safety and efficacy of XS0601 in preventing restenosis following percutaneous coronary intervention (PCI). Methods A multi-center, randomized, double-blind, placebo-controlled trial was conducted. A total of 335 patients were randomized into treatment with the oral administration of XS0601, or a placebo for 6 months after successful PCI. Angiographic follow-up was scheduled at 6 months, and clinical follow-ups performed at 1, 3 and 6 months after PCI. The primary end point was angiographic restenosis. The secondary end points were the combined incidence of death, target lesion nonfatal myocardial infarction, repeat angioplasty, and coronary artery bypass graft surgery.Results A total of 308 patients (91.9%) completed the study and 145 cases (47.1%) received angiographic follow-up. The restenosis rates were significantly reduced in the XS0601 group as compared with the placebo group (26.0% vs. 47.2%, P < 0.05), and the minimum lumen diameter (MLD) was greater [(2.08 ± 0.89) mm for XS0601 vs. (1.73 ± 0.94) mm for placebo, P < 0.05]. XS0601 also significantly reduced the combined incidence of major adverse cardiac event (10.4% in the XS0601 group vs. 22.7% in the placebo group, P < 0.05). The incidence of recurrent angina at 3 and 6 months after PCI was also significantly reduced in XS0601 group (7.1% and 11.0%) as compared with those in placebo group (19.5% and 42.9%) (P < 0.05). No significant side effects occurred within the 6-month follow-up period in the XS0601 group.Conclusion Administration of XS0601 for 6 months is demonstrated to be safe and effective in reducing restenosis in post-PCI patients.