Abstract: A rapid method was developed for the simultaneous multi-residue determination of 48 veterinary drugs in eggs by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)with pass-through solid phase extraction(SPE). The samples were extracted with 90% acetonitrile-water mixtures. The extraction cleaned up with an Oasis PRiME HLB SPE cartridges was determined by liquid chromatography-tandem mass spectrometry in positive and negative ionization mode using an electrospray ionization source with the multiple reaction monitoring mode. Quantitative was achieved by an external calibration procedure using matrix-matched standard solutions. The chromatographic separation was achieved on a CAPCELL PAK C18 MGⅢ-H chromatographic column using 0.05%(v/v)formic acid acetonitrile solution and aqueous 0.1%(v/v)formic acid solution gradient as the mobile phase in the positive ion mode;And on a ACQUITY UPLC BEH C18 column using acetonitrile and 5 mmol/L ammonium acetate aqueous solution gradient as the mobile phase in the negative ion mode. The results showed that the linearities of the 48 veterinary drug residues in 0.5~50 μg/kg had the correlation coefficient and the correlation coefficient were from 0.9952 to 1.0000. The limits of detection(LOD)ranged from 0.01 to 0.55 μg/kg and the limits of quantification(LOQ)ranged from 0.03 to 1.83 μg/kg. The recoveries was 63.3%~111.4%,while the relative standard deviations was less than 10%.The proposed method is sensitive,accurate,and efficient. It is applicable for rapid screening and quantification of 48 veterinary drug residues in eggs.