Density functional theory calculations are performed to investigate the hydrodesulfurization (HDS) mechanisms of different sulfur-containing compounds, such as thiophene, benzothiophene, dibenzothiophene (DBT) and 4,6-dimethyldibenzothiophene (4,6-DMDBT) on the brim and CUS sites. Based on the systematic calculations, the dominant reaction pathway of different molecules are explored, and the structure-activity relationship of brim and CUS sites is mainly discussed under the real reaction conditions (p(H2) = 4 MPa, T = 650 K). According to the DFT calculation results, brim site is more favorable for the HDS reactions of thiophene and benzothiophene. However, both brim and CUS sites are considered to participate in the DBT and 4.6-DMDBT HDS processes. The brim site provides the hydrogenation active sites, and the CUS site promotes the removal of sulfur atoms. The proposed mechanism strongly supports that the brim and CUS sites act in synergistic effect for the HDS reaction of the highly refractory organic sulfides.