Abstract: A method of solid phase extraction-ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been established for the simultaneous determination of 4 alkylresorcinols in Massa Medicata Fermentata, including 5-pentadecyl resorcinol (AR-15), 5-heptadecylresorcinol (AR-17), 5-nonadecylresorcinol (AR-19) and 5-heneicosylresorcino (AR-21). The analysis was performed on a Brownless Spp C₁₈ column (2.1 mm×100 mm, 2.7 μm) with the mobile phase of 5 mmol/L ammonium acetate solution in phase A and formic acid:acetonitrile solution (volume ratio of 1:1000) in phase B at a flow rate of 0.5 mL/min with gradient elution. The column temperature was 35 ℃, and the electron spray ionization source was adopted in negative ion scanning with multiple reaction monitoring mode. Combined with principal component analysis and orthogonal partial least square-discriminant analysis, the main chemical components affecting the quality of Massa Medicata Fermentata before and after processing were found. The results showed that 4 components had good linear relationships in their respective ranges (r＞0.992 6), the average spiked recoveries ranged from 99.36% to 101.36%, and the relative standard deviations (RSD) were 0.85%~2.10%. The mass difference substance was AR-21 that caused the main difference through chemical pattern recognition analysis. The method is simple, feasible, stable and reliable, and can be used for the quality control of different products of Massa Medicata Fermentata.