Objective: To evaluate the efficacy and safety of Chinese medicine(CM) plus Western medicine(WM) in the treatment of pediatric patients with severe hand, foot and mouth disease(HFMD) by conducting a prospective, controlled, and randomized trial. Methods: A total of 451 pediatric patients with severe HFMD were randomly assigned to receive WM therapy alone(224 cases, WM therapy group) or CM [Reduning Injection(热毒宁注射液) or Xiyanping Injection(喜炎平注射液)] plus WM therapy(227 cases, CM plus WM therapy group) for 7–10 days, according to a web-based randomization system. The primary outcome was fever clearance time, which was presented as temperature decreased half-life time. The secondary outcomes included the rate of rash/herpes disappearance within 120 h, as well as the rate for cough, runny nose, lethargy and weakness, agitation or irritability, and vomiting clearance within 120 h. The drug-related adverse events were also recorded. Results: The temperature decreased half-life time was 40.4 h in the WM therapy group, significantly longer than 27.2 h in the CM plus WM therapy group(P<0.01). Moreover, the rate for rash/herpes disappearance within 120 h was 43.6%(99/227) in the CM plus WM therapy group, significantly higher than 29.5%(66/224) in the WM therapy group(P<0.01). In addition, the rate for cough, lethargy and weakness, agitation or irritability disappearance within 120 h was 32.6%(74/227) in the CM plus WM therapy group, significantly higher than 19.2%(43/224) in the WM therapy group(P<0.01). No drug-related adverse events were observed during the course of the study. Conclusions: The combined CM and WM therapy achieved a better therapeutic efficacy in treating severe HFMD than the WM therapy alone. Reduning or Xiyanping Injections may become an important complementary therapy to WM for relieving the symptoms of severe HFMD. Objective: To evaluate the efficacy and safety of Chinese medicine (CM) plus Western medicine (WM) in the treatment of pediatric patients with severe hand, foot and mouth disease (HFMD) by conducting a prospective, controlled, and randomized trial. Methods: A total of 451 pediatric patients with severe HFMD were randomly assigned to receive WM therapy alone (224 cases, WM therapy group) or CM [Reduning Injection or Xiyanping Injection] plus WM therapy (227 cases, CM plus WM therapy group) for 7-10 days, according to a web-based randomization system. The primary outcome was fever clearance time, which was presented as temperature decreased half-life time. rate of rash / herpes disappearance within 120 h, as well as the rate for cough, runny nose, lethargy and weakness, agitation or irritability, and vomiting clearance within 120 h. The drug-related adverse events were also recorded. Results: The temperature decreased half-life time was 40.4 h in the WM therapy group, significantly longer than 27.2 h in the CM plus WM therapy group (P <0.01). Moreover, the rate for rash / herpes disappearance within 120 h was 43.6% (99/227 ) significantly higher than 29.5% (66/224) in the WM therapy group (P <0.01). In addition, the rate for cough, lethargy and weakness, agitation or irritability disappearance within 120 h was Significantly higher than 19.2% (43/224) in the WM therapy group (P <0.01). No drug-related adverse events were observed during the course of the study Conclusions: The combined CM and WM therapy achieved a better therapeutic efficacy in severe HFMD than the WM therapy alone. Reduning or Xiyanping Injections may become an important complementary therapy to WM for relieving the symptoms of severe HFMD.