Methanol-to-DME conversion over ZSM-22 Brønsted acid sites is investigated on the basis of periodic density functional theory calculations. DME formation has been speculated to take place via the dissociative or associative pathway. It is shown that the dissociative pathway is the predominant pathway. We find that water lowers the activation energies of key reactions but that the lowering of the activation energies is insufficient to increase the rate because of the entropy loss associated with water adsorption. The consequence of acid strength on the methanol-to-DME conversion pathways is investigated on the basis of Al-, Ga-, or In-induced Brønsted acid sites. We show that linear correlations between activation energies and acid strength exist. It is found that weaker acidity leads to higher activation energies. We find that changes in acidity will not change the conclusion that the dissociative pathway is the predominant pathway.