Objective To evaluate the efifcacy and safety of Xiyanping in the treatment of hand-foot and mouth disease. Methods Based on the principles and methods of Cochrane systematic reviews, Cochrane Library, PubMed, Medline, Chinese Bio-medicine Database (CBM), China Journal Full-text Database (CNKI), VIP database and Wanfang database were searched. All of the randomized controlled trials (RCT) of Xiyanping versus ribavirin were included. The data were extracted and evalu-ated by two reviewers independently. Risk assessment tool was used to assess the risk of bias and software Revman5.0 was used for meta-analysis. Results Twenty-four RCT and 3314 patients were included. Comparing to ribavirin, Xiyanping showed better therapeutic outcomes regarding to total effective rate, durations of fever and rash elimination (RR=1.17, 95%CI:1.12~1.23;MD=-1.56, 95%CI:-2.10~-1.02;MD=-1.41, 95%CI:-1.90~-0.93). Side effects were rare in both groups and could be recovered after drug withdrawal. Conclusions The current evidence suggests that Xiyanping is superior to ribavirin in the treatment of hand-foot and mouth disease.