A series of CoMoS catalysts supported on hexagonal mesoporous silica (HMS) modified with different amounts of phosphate (0.5, 1.0, 1.5 and 2.0 wt.%) were prepared in order to study the influence of phosphate on catalyst deactivation. The catalysts were characterized by a variety of techniques (X-ray fluorescence, N2 adsorption–desorption at 77 K, FT-IR study of the framework vibration and NO adsorption, NH3-TPD, H2–TPR, XPS, 31P NMR and TPO/TGA). The sulfided catalysts were tested in the deep hydrodesulfurization (HDS) of 4,6-dimethyldibenzothiophene (4,6-DMDBT) performed in a fixed-bed flow reactor at 598 K, P = 5.0 MPa and WHSV = 46.4 h−1. The catalyst with the largest phosphate content (2.0 wt.%) showed the best catalytic response linked with its low deactivation during on-stream reaction and a larger sulfidation degree of Co species. It was found that coking behavior is closely related with the location of the active sites in the support structure being a lower coke formation on the catalysts having active phases located within support structure. The catalysts modified with a large amount of phosphorous (1.5 and 2.0 wt.% of P2O5) were more susceptible to coking and produced a more polymerized coke than P-free sample, as confirmed by TPO/TGA experiments. The presence of P2O5 favours the sulfidation degree of Co species and the creation of medium strength acid sites leading to the enhancement of the 4,6-DMDBT HDS reaction toward the isomerization route.