A rapid and sensitive high-performance liquid chromatography-mass spectrometry method was established to determine the trace residues of piperazine in vortioxetine hydrobromide. The presence of piperazine was determined by precolumn derivatization with dansyl chloride. Chromatographic separation was performed on a Waters SunFire C8 column (150 × 4.6 mm, 3.5 μm) in gradient elution mode, using formic acid and acetonitrile as mobile phase. Detection was performed in a single quadrupole mass spectrometer in single ion monitoring mode using positive ionization. An m/z value of 553 was selected for monitoring disubstituted piperazine by DNS-Cl. Linearity, accuracy, and precision were found to be acceptable over the piperazine concentration range of 0.3525 - 2.35 ng mL-1. The limit of detection and limit of quantification of piperazine were 0.1175 and 0.3525 ng mL-1, respectively, which complied with the requirements of qualitative and quantitative analyses. The method was deemed sensitive and efficient.