Objective To systematically review the effectiveness and safety of Tanreqing for curing the hand-foot-mouth disease. Methods Such databases as PubMed, EMbase, CENTRAL, CBM, CNKI, VIP and WanFang Data are electronically searched to collect the randomized controlled trials (RCTs) on the effectiveness and safety of Tanreqing for hand-foot-mouth disease till February 2013. According to the inclusion and exclusion criteria, literature was screened, data were extracted, and the methodological quality of included studies was also assessed. Then, meta-analysis was performed using RevMan 5.2.7 software. Results Twelve RCTs on Tanreqing versus ribavirin involving 1 258 cases and 27 RCTs on Tanreqing plus ribavirin versus ribavirin involving 3 289 cases were included. The results of meta-analysis showed that, compared to ribavirin, Tanreqing has higher total efficiency in the treatment of hand-foot-mouth disease (OR=5.03, 95%CI 3.28 to 7.71, Plt;0.000 01), cooling time (MD= –1.09, 95%CI –1.51 to –0.68, Plt;0.000 01), simplex regression time (MD= –0.90, 95%CI –1.20 to –0.60, Plt;0.000 01), and healing time (MD= –1.76, 95%CI –2.52 to –0.99, Plt;0.000 01), with significant differences. Compared to ribavirin, the group of Tanreqing plus ribavirin has higher total efficiency on treatment of hand-foot-mouth disease (OR=5.32, 95%CI 4.02 to 7.06, Plt;0.000 01), cooling time (MD= –1.32, 95%CI –1.63 to –1.01, Plt;0.000 01), simplex regression time (MD= –0.5, 95%CI –0.98 to –0.2, Plt;0.000 01), and healing time (MD= –1.41, 95%CI –1.83 to –0.98, Plt;0.000 01), with significant differences. The results of indirect comparative analysis showed that, there was no significant difference in the treatment options of Tanreqing plus ribavirin and Tanreqing alone concerning total efficiency, cooling time, simplex regression time, and healing time. Conclusion The study shows that Tanreqing alone and Tanreqing plus ribavirin are similar for curing the hand-foot-mouth disease, and both groups have better clinical effectiveness than ribavirin alone.