Abstract: Objective To evaluate the efficacy and safety of Dextromethorphan Hydrochloride, Chlorphenamine Malente, and Ammonium Chloride Syrup on eliminating or relieving the symptoms of acute upper respiratory infections in children, by comparing with Guaifenesin, Dextromethorphan Hydrobromide, Methylephedrine Hydrochloride, and Chlorphenamine Maleate Syrup. Methods Random, blind and parallel control method was adopted. A total of 253 pediatric patients were recruited in 11 clinical research centers; 127 patients were assigned in experimental group and finally 118 patients were included in the program set analysis (PPS); 126 patients were assigned into control group and finally 116 patients were included in PPS. The experimental group took Dextromethorphan Hydrochloride, Chlorphenamine Malente, and Ammonium Chloride Syrup and control group took Guaifenesin, Dextromethorphan Hydrobromide, Methylephedrine Hydrochloride, and Chlorphenamine Maleate Syrup. All of the patients took as prescribed at least for 3 days but not more than 7 days. Results There was no significant differences in age, sex, and acute upper respiratory tract infection scores between the two groups (P?>?0.05). PPS showed the median time of symptom relief of acute upper respiratory tract infection in experimental group was 51.0 h (95%CI: 43.0-62.0 h) and 56.0 h (95%CI: 48.0-64.0 h) in control group. There was no difference between two groups (P?>?0.05). After calibration of center and baseline effects, the experimental group was not worse than the control group. There was no difference in the score of acute upper respiratory tract infection between two groups (F=0.14, P=0.710). The individual symptoms disappear rate of acute upper respiratory tract infection and the compliance between two groups were similar (P all?>?0.05). Both groups had 7 cases of adverse events, and one case of adverse drug reactions each. Thus, the adverse reaction rates in two groups were 0.8% each. Conclusions Dextromethorphan Hydrochloride, Chlorphenamine Malente, and Ammonium Chloride Syrup can effectively relieve symptoms rapidly in the treatment of children with acute upper respiratory tract infection, and its efficacy and safety were non worse than traditional Guaifenesin, Dextromethorphan Hydrobromide, Methylephedrine Hydrochloride, and Chlorphenamine Maleate Syrup.