The hydrolysis of acetonitrile has been studied theoretically by different ab initio methods (RHF, DFT, and MP2). Two Brønsted acid catalysts have been compared: zeolite and HCl(H2O)x=2,1 clusters. Some interesting analogies have been found for the reaction path catalyzed by these different acids, especially in the hydration transition state. The size and the configuration of a zeolite cluster model have an important influence on predicting the reaction mechanism. The van der Waals interactions also play an important role in this reaction. Due to these interactions, oxygen atoms of the zeolite cavity can stabilize charged species as N- and O-protonated acetamide configurations. For the zeolite catalyst, the rate-limiting step of the overall reaction is the hydration of acetonitrile. On the other hand, in the hydrochloric acid catalysis, the rate-limiting step is either the hydration or the isomerization step. Acetamide appears to be the most stable species adsorbed on zeolite and it is responsible for poisoning the reaction.