Parasites lack the ability to synthesize purines de novo. Instead, they use an enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase), to salvage host purine and to construct their own nucleotides. In this paper, we investigate the reaction mechanism of the HGXPRTase from Plasmodium falciparum using free-energy simulations and a hybrid potential QM/MM description of the enzyme. The possibility of both dissociative and associative nucleophilic substitutions is discussed, as contradictory hypotheses have been postulated on the basis of crystallographic data and kinetic isotope effect experiments. The preferred pathway is predicted to be stepwise with a rapid proton transfer from the hypoxanthine to the protein followed by a rate-limiting glycosyl transfer. This latter step has a D(N)A(N) mechanism with a transition state in which the pyrophosphate leaving group is more closely bound than the attacking hypoxanthine nucleophile. The energy barrier is comparable to the experimentally observed one.