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Rationale: In order to characterize the intracellular pharmacokinetic properties of tigecycline, we developed and fully validated a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantification of tigecycline in human lung epithelial (BEAS‐2B) cells and polymorphonuclear neutrophils (PMNs). Methods: Tetracycline was used as an internal standard and chromatographic separation was achieved on a C18 Hypersil Gold aQ column using two mobile phases, a solution of water (containing 0.1% formic acid) and acetonitrile. The flow rate was 0.4 mL/min for 5.0 min. Tigecycline drug uptake was evaluated by incubating the BEAS‐2B cells and the PMNs for up to 3 h at tigecycline concentrations of 1 mg/L. Results: The assay was linear over the tested concentration range of 0.01–2 mg/L for tigecycline in BEAS‐2B cells and PMNs (r2 >0.99). The inter‐ and inter‐day precisions (RSD, %) were <10.02% and the accuracies (%) were within the range of 85–115%. The uptake study showed that after incubation with tigecycline (1 mg/L) for 3 h at 37°C, the intracellular peak concentration of BEAS‐2B cells was 14.44 ± 7.12 mg/L at 1 h, and 41.43 ± 25.66 mg/L in PMNs at 20 min. The mean intracellular concentrations fluctuated in the range of 0.8–14.44 mg/L in BEAS‐2B cells and 10.14–41.43 mg/L in PMNs for 1 mg/L tigecycline exposure. Conclusions: Validated LC/MS/MS is a simple, rapid, and sensitive method for determining the intracellular concentration of tigecycline, and tigecycline has good penetrations both in human BEAS‐2B cells and PMNs. The method can be efficiently used for future studies of the intracellular pharmacokinetics of tigecycline. [ABSTRACT FROM AUTHOR]