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Voriconazole is used to prevent invasive pulmonary aspergillosis. However, little is known about the concentrations of voriconazole in human lung epithelial cells (A549), which is the target for preventing invasive pulmonary aspergillosis. The goal of this study was to develop a high-performance liquid chromatography–tandem mass spectrometry method to quantify voriconazole in A549 cells. A triple-quadrupole mass spectrometer in selected reaction monitoring mode was used with positive electrospray ionization. The total duration of each run was 5 min. The calibration curves fit a least squares model for the voriconazole concentration ranging from 0.625 to 160 ng/mL. Intraday and interday coefficients of variation were less than 10%. Recoveries at the concentrations of the quality control samples where greater than 85%, and the matrix effects showed that the ratios of the peak response exhibited a 15% suppression of the signal in the matrix compared to water. Voriconazole may penetrate A549 cells. However, the voriconazole uptake was slow in A549 cells, reaching a plateau at 2 h, where the dose-dependent intracellular voriconazole concentrations were 1.98 ± 0.38, 4.43 ± 0.54, and 8.14 ± 0.52 ng/mg protein for extracellular voriconazole concentrations of 5, 10, and 20 µg/mL, respectively. The uptake of voriconazole by A549 cells was linear at extracellular concentrations from 0 to 20 µg/mL. This study established a rapid and sensitive method suitable for determining voriconazole in A549 cells and described the kinetic properties of the absorption of voriconazole by A549 cells. [ABSTRACT FROM PUBLISHER]