With the employment of solid phase extraction and high performance liquid chromatography tandem mass spectrometry（HPLC-MS/MS），a method was developed for the determination of 21 antibiotics，including twelve sulfonamides，four quinolones，three tetracyclines，roxithromycin and trimethoprim，in hospital wastewater.In the acid condition，target compounds were enriched with Oasis HLB column and purified with 10% menthol.The analytes were eluted with methanol，and subsequently quantified by HPLC-MS/MS under multi-reaction monitoring（MRM） mode.Under the optimal conditions，the calibration curves of all 21 targets were linear in the range of 1.0-500 μg/L with correlation coefficients more than 0.99.The spiked recoveries at two levels of 0.05 μg/L and 1.0 μg/L were in the ranges of 71%-105% and 76%-111%，respectively,with relative standard deviations（RSDs） less than 15%.The method detection limits varied between 0.005 μg/L and 0.022 μg/L.The average recoveries of 21 antibiotics in the hospital wastewater samples ranged from 71% to 135%,with RSDs less than 25%.This method was simple，rapid and accurate，and could meet the requirements for monitoring on antibiotics residues in hospital wastewater.