Abstract: The method for simultaneous determination of 21 sulfonamide residues in honey was developed by Ultra high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS). Deuterium substituted standards were used as internal standards and added to the sample before extraction. The sample was dissolved by buffer solution (pH=4.00); extracted with 1% formic acid in acetonitrile; purified by salting-out and cleaned up by NH2 adsorbent. The mass spectrometer was operated in the positive ion mode using multiple-reaction monitoring for qualitative and quantization. The detection limit of the method was 0.12-2.46 μg/kg. The correlation coeficient of linear calibration curve was over 0.99 within the range of sulfonamides concentration 0.05-60 ng/mL. The average recoveries for 21 sulfonamide residues were 60.44%-107.80%. The method is simple、rapid、reliable、stable and sensitive. It's suitable for high throughout determination of 21 sulfonamide residues in honey.