Abstract: A sensitive and specific HPLC-MS/MS method is developed for the determination of sibutramine and its two active metabolites in human plasma. Plasma samples are extracted with ethyl ether and separated on an ALLTIMA C18 column with 5 mmol ammonium acetate-0.2% formic acid-methanol as the mobile phase. Detection is performed on a tandem mass spectrometry in multiple reaction monitoring (MRM) mode. The limits of determination quantitatively of sibutramine and its two metabolites are 0.05 μg/L. The weighted calibration curve is linear in the range of 0.05~25 μg/L. Inter- and intra-day relative standard deviation of sibutramine and its two metabolites are all within ±15% and the accuracies are within 92.7%~103.0%. The method will be applied to the pharmacokinetic study of sibutramine and its metabolites in Chinese healthy volunteers.