Modeling of the glutathione peroxidase-like activity of phenylselenol has been accomplished using densityfunctional theory and solvent-assisted proton exchange (SAPE). SAPE is a modeling technique intended to mimic solvent participation in proton transfer associated with chemical reaction. Within this method, explicit water molecules incorporated into the gas-phase model allow relay of a proton through the water molecules from the site of protonation in the reactant to that in the product. The activation barriers obtained by SAPE for the three steps of the GPx-like mechanism of PhSeH fall within the limits expected for a catalytic system at physiological temperatures (Delta G(1)(double dagger), = 19.1 kcal/mol; Delta G(2)(double dagger) = 6.6 kcal/mol; G(3)(double dagger) = 21.7 kcal/mol) and are significantly lower than studies which require direct proton transfer. The size of the SAPE network is also considered for the model of the reduction of the selenenic acid, step 2 of the GPx-like cycle. Use of a fourwater network better accommodates the reaction pathway and reduces the activation barrier by 5 kcal/mol over the two-water model.