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A ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry method for the determination of antibiotics drug residues in tilapia was developed using dispersed solid phase extraction as sample preparation method. The matrixmatched standard calibration method was used for quantitation. The results showed great reduction of the matrix effect with corrected matrix factor ranging 0.84~1.17 for 9 antibiotics. Within the linear range, the correlation coefficients(R2)of the calibration curves for the compounds were greater than 0.90. The average recoveries in blank tilapia ranged from 78.04%~103.08%, with intra-and inter-day relative standard deviation(RSD)ranged from 1.37%~9.86%and 3.86%~9.92%, respectively. The limit of detection(LOD)and limit of quantification(LOQ)of the method ranged from 0.31~16.37μg/kg and 1.04~54.56μg/kg, respectively. The method developed in the present study had the advantages of simple operation, less matrix interference, high recovery rate and good repeatability. So it could be used for the detection of multi-antibiotics in tilapia and provide some technical support for food safety supervision. [ABSTRACT FROM AUTHOR]