Abstract: Rare earth element combined with mass spectrometry has received extensive attention in recent years because of their high chelating efficiency, chromatographic behavior, ionization efficiency, low background and no interference of excessive metal ions. Monoisotopic elements of terbium (Tb), yttrium (Y), thulium (Tm), holmium (Ho) and lutetium (Lu) were selected as model in this research, and the synthesis of peptides and digestion products from proteins through the bifunctional reagent DTPA double anhydride was investigated. The labeling conditions were optimized, followed by the examination of chromatographic behavior, co-elution, stability, ion replacement, dynamic range and mass detection limits. The results show that thulium and holmium have the best binding efficiency of 92.5% and 89.9%, respectively. Stability test results show that 95% of the quality tags have been detected in a week when stored at 4 ℃. Better linear relationship can be gotten when the concentration of metal particles within 6 times. The ion exchange results show that only a small part of the ion exchange takes place, and it has no effect on the labeling experiments.