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Objective A simple, sensitive, and rapid LC-MS/MS method has been established and validated for the determination of liquiritigenin(LG) in rat plasma. Methods Naringenin was chosen as internal standard(IS). LG and IS were separated on a Diamonsil C18 analytical column with a mobile phase of methanol-10% methanol in water containing 0.5 mmol/L ammonium formate and 0.2% formic acid(55:45) at the isocratic flow rate of 0.6 m L/min for 10 min. The multiple reaction monitoring(MRM) was performed on a mass spectrometer in the negative ion mode with electro-spray ionization(ESI) source and the transition from precursor ion to product ion was m/z 255.0→119.0 for LG and m/z 271.0→151.0 for IS, respectively. Results The linearity was acceptable in the range of 5-5000 ng/m L(r = 0.9973). The inter-day and intra-day accuracies were in the ranges of-0.09%-3.25% and-5.02%-9.21%, respectively. The precision was in the ranges of 3.60%-12.4% and 0.909%-6.89%, respectively. LG was stable in the course of analysis and storage. Conclusion The LC-MS/MS method was successfully applied to the pharmacokinetic study for the first time in rats after ig and iv administration of liquiritin(LQ), a glycoside of LG, at pharmacologically effective levels.