The kinetics of the butyl tert-butyl ether (BTBE) synthesis reaction over Amberlyst™ 35 as the catalyst has been studied at 303–356 K in the liquid phase in two different reactor systems: batch and fixed-bed. Internal mass transfer effects were detected at temperatures above 333 K for catalyst particles larger than 0.25 mm. Particles smaller than 0.08 mm did not show mass transfer limitations under the whole assayed temperature range. The best kinetic model has been searched among a large number of kinetic equations resulting from the systematic combination of all possible elementary reactions, adsorbed species, and rate-determining step based, according to the Langmuir–Hinshelwood–Hougen–Watson and the Eley–Rideal formalisms. The significance of the temperature effect on the kinetic parameters and of the effect of the interaction between the catalyst and the reaction medium on the reaction rate has been checked. All proposed kinetic equations have been fitted to experimental rate data free from mass transfer limitations. The model discrimination procedure has been based on mathematical and physicochemical criteria. The resulting kinetic model is consistent with an Eley–Rideal type mechanism where one 1-butanol molecule adsorbs on one active site of the catalyst, it reacts with one isobutene molecule from the liquid phase to give one adsorbed BTBE molecule, which finally desorbs. The rate-determining step is the surface reaction. The catalyst activity is affected by the resin-medium interaction. 1-Butanol adsorption on the catalyst is more exothermic than BTBE adsorption, and isobutene adsorption is negligible.