Abstract: Synthetic cathinones, the designer analogs of the naturally occurring cathinone found in Khat, largely entered the recreational drug market at the end of the 2000s. They are a large class of new psychoactive substances (NPS) often used as substitutes for cocaine, which may cause psychostimulant and hallucinogenic effects and a number of fatalities worldwide. N-Ethylpentylone, one of the most famous synthetic cathinones on the clandestine market, was controlled in China since September 1, 2018. Recently, three uncontrolled isomers of N-ethylpentylone, namely hexylone, dipentylone and N-propylbutylone, were identified in the suspected samples. In order to investigate the mass fragmentation characteristics of synthetic cathinones with similar chemical structures, the four isomers were analyzed using gas chromatography-Orbitrap mass spectrometry (GC-Orbitrap-MS) and ultra high performance liquid chromatography-quadrupole time of flight-mass spectrometry (UPLC-QTOF-MS). High-resolution mass spectra were obtained by electron impact (EI) and electrospray ionization-collision induced dissociation (ESI-CID), and the structures and fragmentation pathways of main product ions were deduced. Under the EI mode, four isomers presented similar mass spectra with same base peak ion C₆H₁₄N⁺, which was originated from the α-cleavage of the C—N bond, the dominant fragmentation pathway of all synthetic cathinones. C₈H₅O₃⁺ and C₇H₅O₂⁺, the characteristic ions of cathinones with methylenedioxy substituted phenyl ring in the molecular structure, were also observed for all of them. However, there were variances in the low m/z ions generated by further cleavage of C₆H₁₄N⁺. Under the ESI-CID mode, the mass spectra were significantly different from each other, hence the alkyl substitution at different positions could be determined through the fragment ions generated by loss of H₂O, amino groups and other groups from M+H⁺. By investigating the mass spectrometric characteristics of the four isomers, their key distinguishing features were summarized, which provided a reference for the identification of synthetic cathinone, especially the substances with similar chemical structures.