OBJECTIVE： To establish a method for simultaneous determination of ephedrine hydrochloride， nitrofural and diphenhydramine hydrochloride in Compound diphenhydramine nasal drop. METHODS： RP-HPLC method was adopted. The determination was performed on Inertsil ODS-3 C18 column with mobile phase consisted of 0.05 mol/L potassium dihydrogen phosphate buffer （pH 7.0）-acetonitrile （gradient elution） with flow rate of 1.0 mL/min. The detection wavelength was set at 256 nm， and the column temperature was 35 ℃. The sample size was 20 μL. RESULTS： The concentrations of phedrine hydrochloride， nitrofural and diphenhydramine hydrochloride ranged 122.1-366.3 μg/mL（r＝0.999 9）， 5.2-15.5 μg/mL（r＝0.999 8）and 31.5-94.5 μg/mL（r＝0.999 4）， respectively. The limits of quantitation were 2.442， 0.010， 2.520 μg/mL， and the limits of detection were 0.810， 0.003， 0.830 μg/mL， respectively. RSDs of precision， stability and reproducibility tests were lower than 1.0％. The recoveries of them were 99.2％-101.7％ （RSD＝0.9％，n＝9）， 96.4％-102.0％％ （RSD＝1.7％，n＝9）， 100.2％-101.9％（RSD＝0.4％，n＝9）， respectively. CONCLUSIONS： The method is simple， accurate and reproducible， and can be used for simultaneous determination of ephedrine hydrochloride， nitrofural and diphenhydramine hydrochloride in Compound diphenhydramine nasal drop.