The homodimeric myeloperoxidase (MPO) features a histidine as a proximal ligand and a sulfonium linkage covalently attaching the heme porphyrin ring to the protein. MPO is able to catalyze Cl- oxidation with about the same efficiency as chloroperoxidase at pH 7.0. In this study, we seek to explore the parallels and differences between the histidine and cysteine heme-dependent halogen peroxidases. Transition states, reaction barriers, and relevant thermodynamic properties are calculated on protein models. Together with electronic structure calculations, it gives an overview of the reaction mechanisms and of the factors that determine the selectivity between one- and two-electron paths. Conclusions point to the innate oxidizing nature of MPO with the ester and sulfonium linkages hiking up the reactivity to enable chloride oxidation. The installation of a deprotonated imidazolate as a proximal ligand does not shift the equilibrium from one- to two-electron events without influencing the chemistry of the oxidation reaction.