A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of donepezil in human plasma samples. Diphenhydramine was used as the internal standard. The collision‐induced transition m/z 380 → 91 was used to analyze donepezil in selected reaction monitoring mode. The signal intensity of the m/z 380 → 91 transition was found to relate linearly with donepezil concentrations in plasma from 0.1–20.0 ng/mL. The lower limit of quantification of the LC/MS/MS method was 0.1 ng/mL. The intra‐ and inter‐day precisions were below 10.2% and the accuracy was between −2.3% and +2.8%. The validated LC/MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 5 mg donepezil hydrochloride. The non‐compartmental pharmacokinetic model was used to fit the donepezil plasma concentration‐time curve. Maximum plasma concentration was 12.3 ± 2.73 ng/mL which occurred at 3.50 ± 1.61 h post‐dosing. The apparent elimination half‐life and the area under the curve were, respectively, 60.86 ± 12.05 h and 609.3 ± 122.2 ng · h/mL. LC/MS/MS is a rapid, sensitive and specific method for determining donepezil in human plasma samples. Copyright © 2006 John Wiley & Sons, Ltd.