Abstract: Based on the characteristics of ginseng samples matrix, a method for simultaneous determination of azoxystrobin, difenoconazole, imidacloprid, indoxacarb and thiazinone residues in ginseng was established by multi-plug filtration cleanup (m-PFC) method combined with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). A low detection limits (LOD, 0.03-0.18 μg/kg) and quantitative limits (LOQ, 0.11-0.59 μg/kg) were obtained. The LOQ is three orders lower than the limit for azoxystrobin (1 mg/kg) and difenoconazole (0.5 mg/kg) in ginseng in GB 2763—2016. The linear range for five pesticides can reach to 1-500 μg/L. The average recovery rate of the method was between 76% and 115%, with RSD less than 11% at the spiking levels of 2, 10, 50, 100 and 300 μg/kg. Compared with the traditional sample pretreatment method, the new method has the advantages of simple operation, time-saving, labor-saving, and high sensitivity. The method was successfully applied to the detection of five pesticides in six ginseng samples. No corresponding pesticide residues were detected. This method provides a direction for rapid and accurate detection of pesticide residues in ginseng. It also provides a reference for revising the maximum residue limits of pesticides in ginseng in the national standard.