Ginsenoside compound K(GCK), the main metabolite of protopanaxadiol constituents of Panax ginseng, easily produces alkali metal adduct ions during mass spectrometry particularly with lithium. Accordingly, we have developed a rapid and sensitive liquid chromatography–tandem mass spectrometric method for analysis of GCK in human plasma based on formation of a lithium adduct. The analyte and paclitaxel(internal standard) were extracted from 50 m L human plasma using methyl tertbutyl ether. Chromatographic separation was performed on a Phenomenex Gemini C18 column(50 mm 2.0 mm; 5 μm) using stepwise gradient elution with acetonitrile–water and 0.2 mmol/L lithium carbonate at a flow rate of 0.5 m L/min. Detection was performed in the positive ion mode using multiple reaction monitoring of the transitions at m/z 629-449 for the GCK-lithium adduct and m/z 860-292 for the adduct of paclitaxel. The assay was linear in the concentration range 1.00–1000 ng/m L(r~2>40.9988)with intra- and inter-day precision of ±8.4% and accuracy in the range of 4.8% to 6.5%. Recovery,stability and matrix effects were all satisfactory. The method was successfully applied to a pharmacokinetic study involving administration of a single GCK 50 mg tablet to healthy Chinese volunteers.