Zeolite Y-supported Co sulfide catalysts were prepared by using different supports (NaY or CaY) and precursors (CoCl2 or Co(CO)3NO) to prevent the negative effect on the thiophene HDS activity caused by protolysis. It appeared that protolysis could be retarded by partially blocking the sodalite cages with Ca2+ cations. The catalysts were prepared via gas phase adsorption (Co(GPA)NaY) and via ion exchange (CoNaY and CoCaY). They differ in amount of protons after sulfidation, which make the study of synergetic effect of protons on the thiophene HDS activity possible. It turned out that in zeolite-supported metal sulfides (Co or Ni) prepared by ion exchange an interaction exists between protons and the metal sulfide, resulting in a high dispersion and consequently a high activity. However, the industrial applications of this type of catalysts may be limited because bases like NH3 and H2O disturb the metal sulfide–proton interaction, resulting in loss of dispersion. The synergetic effect between protons and metal sulfide cannot be explained only by an improvement of dispersion. Possibly, the protons themselves play an active role in the HDS reaction or act as a structural promoter by, e.g., increasing the electron deficient character of the metal sulfide.