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Nowadays, the analysis of the multi-components in Chinese patent medicine prescriptions is being paid more attention. Therefore, in this study for the first time, a simple, rapid ultrahigh performance liquid chromatography–electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) method was established for simultaneous determination of 18 active compounds in a Chinese patent medicine of Hu Gan tablets (HGT) from different pharmaceutical factories in China. This task has met great emerging challenges from not only structural complexities and similarities but also co-occurrence of water-soluble and fat-soluble components in HGT. UPLC-ESI-MS/MS was put forward to solve the problems. It was operated in both positive and negative mode using multiple reaction monitoring (MRM). The mobile phase was 0.1% formic acid in water (A) −0.1% formic acid in acetonitrile (B) with linear gradient elution at a flow rate of 0.2 mL/min, run for a total of 12.0 min. The optimized method used provided short analysis time and good linearity (R2 > 0.99), and intra- and inter-day precision (relative standard deviation (RSD) < 4.00%) with good accuracy (94.89–110.03%) and recovery (70.00–126.09%). The results indicate the method could be practically used for quality guarantee of HGT and might also be useful for further studies. [ABSTRACT FROM AUTHOR]