Abstract: A simple and rapid method was developed based on high performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to determine sivelestat and its metabolite XW-IMP-A in human plasma. After a simple protein precipitation, the samples and internal standards were analyzed on a C₁₈ column by a gradient elution program. The mobile phase consisted of 30% acetonitrile in methanol and 5 mmol·L^-1 ammonium acetate at a flow rate of 0.7 mL·min^-1. The mass spectrometric data was collected in multiple reaction monitoring mode (MRM) in the negative electrospray ionization. The standard curves were linear in the range of 10.0-15 000 ng·mL^-1 for sivelestat, and 2.50-1 000 ng·mL^-1 for XW-IMP-A. The low limits of quantitation were identified at 10.0 and 2.50 ng·mL^-1 for sivelestat and XW-IMP-A, respectively. The intra- and inter-day precision were within 11.3% and 13.1% for sivelestat and XW-IMP-A, and accuracy was 0.3% and 0.6% for sivelestat and XW-IMP-A, within the acceptable limits across all concentrations. The method was successfully validated in the pharmacokinetic study of sivelestat in healthy Chinese volunteers.