Abstract: The quadrupole/electrostatic field orbitrap high resolution mass spectrometer was used to directly collect the high precision mass-to-charge ratio (m/z) of the fragment at resolution of 70 000, and the elemental composition of each fragment ion was obtained through element simulation, so as to explore the fragmentation rule of fentanyl drugs. The results showed that the presence of tertiary amine group in the molecular structure of fentanyl drugs made it highly vulnerable to be protonated and formed molecular ion peak M+H⁺. The fragmentation process firstly occured at the C-N bond of the tertiary amine connected to the piperidine ring, that was γ-H from the piperidine ring rearranged onto the carbonyl oxygen attached to tertiary amine group, and the β-bond from the piperidine ring broke (McGannell rearrangement), which formed the neutral-lost molecule and charged fragment at the other end, and the charged fragment was further broken off at high collision energy. The 37 fentanyl drugs and their fragmentation pathways were divided into 3 categories according to their chemical structures. 1 The structure contained the N-phenylacetamide group (149 Da), which could form characteristic fragment ion m/z M+H-149 Da⁺ after the compound neutral lost at 149 Da. 2 The N-phenylacetamide group was replaced by any other non-hydrogen atoms, while the associated piperidine ring-phenylethyl structure remained unchanged, and the compound neutral lost could produce characteristic fragment ion m/z 188.143 3 (C₁₃H₁₈N⁺). Subsequently, the N-C bond between piperidine ring and phenylethyl was further broken to form the characteristic fragment ions m/z 105.070 2 (C₈H₉⁺) and m/z 84.081 4 (C₅H₁₀N⁺). 3 Fentanyl drugs without complete parent nucleus structure, mostly composed of modified N-phenylamide and piperidine ring, which could not be qualitative by the above characteristic fragment ions, but all could be quickly identified by the piperidinyl ring and its product ions m/z 84.081 4 (C₅H₁₀N⁺) and m/z 54.072 4 (C₃H₄N⁺).