Direct synthesis of dimethyl ether from syngas over mixed catalysts constitutes a novel route aimed to replace the traditional two-step process. Many previous studies about this one-step process showed that catalyst deactivation is unavoidable. The present study wants to characterize the deactivation of CuO/ZnO/Al2O3 and gamma-Al2O3 mechanical mixtures, and develop a deactivation model for predicting catalyst performance in presence of deactivation. It was demonstrated that water adsorbs over the gamma-Al2O3 surface, blocking its active sites and causing a sharp conversion drop (mainly observed during the first hours on stream). This effect was reversible and could be avoided by increasing temperature (270 degrees C or above). The other deactivation mechanism was the deposition of carbonaceous species over the catalyst surface. A deactivation model was proposed and fitted to the experimental data.