Abstract: OBJECTIVE To investigate the preventive effect of traditional Chinese medicine TCM and interferon (IFN) on children with hand-foot-and-mouth disease (HFMD)， and to provide scientific TCM recipe and integrated traditional prevention guideline for HFMD in Shandong province. MRTHODS During April 2010 and October 2012's hand-foot-and-mouth disease epidemic seasons， 1106 cases children from the disease focus areas were chosen and randomly divided into four groups: prevention group 1 (TCM group); prevention group 2 (TCM +IFN group); prevention group 3 (IFN group) and control group (Blank control group). The course of treatment is 7 days， every case has been followed-up for 4 weeks. The normal and severe cases were counted， adverse reactions were recorded， and each groups' incidence of HFMD and severe cases were compared. RESULTS The incidences of HFMD in the four groups are separately 8.02%， 11.98%， 9.92% and 36.46%. There is significant difference between every preventive group and control group (all P<0.01). There is no statistical difference between the former three preventive groups (P>0 05). The effective index of preventive groups are separately 4.55， 3.06， 3.68; the protective efficacy of the three groups are separately 78.00%， 67.14%， 72.79%. The average incidence of prevention groups is 9.78%， and severe cases accounted for 6.25% (5/80). The incidence of control group is 36.46%， and severe cases accounted for 17.14% (18/105). CONCLUSION The traditional Chinese medicine and interferon can significantly reduce the incidence of hand-foot-and-mouth disease and the incidence of severe cases.