Abstract: An Ultra-performance liquid chromatography-tandem mass spectrometric(UPLC-MS/MS) method was developed and validated for the determination of residual Kryptofix 2.2.2(K222) in ¹⁸F-labeled radiopharmaceuticals. The chromatographic analysis was performed on a ACQUITY UPLC BEH C₁₈ column (50 mm×2.1 mm×1.7 μm) by a gradient elution, with the run time of about 3 min. The electrospray in positive mode (ESI＋) was used as ionization source of UPLC-MS/MS, and the analysis was performed in the multiple reaction monitoring (MRM) mode. The calibration curve at the spiked concentrations of 2-500 gL－1 for K222 shows good linearity. The intra-day and inter-day errors are not more than ±5%. The accuracy is good, with the deviations between the nominal concentration and calculated concentration of K222 being 80%-120%. The results indicate that the method is rapid, sensitive and reliable for the determination of residual K222 levels in ¹⁸F-labeled radiopharmaceuticals.