We have studied, by means of molecular dynamics (MD) simulations, the effect of two hydrophobic cosolutes, tert-butanol (t-BuOH) and ethanol (EtOH), on the neutral hydrolysis of p-methoxyphenyl dichloroacetate (MPDA) in water. Shifts were calculated in a pre-equilibrium, defined as a spatial distribution of the reacting molecules satisfying specific geometric constraints. The criteria applied represent the configurations from which the reaction can take place (reactive conformation, RC). The shifts induced by the presence of cosolute, as determined from the simulations, correspond well to the experimentally found rate retardations. In accord with experiments, an almost linear correlation between the concentration of added cosolute and the logarithm of the rate constant was found. This is in agreement with a simple mechanistic model. The percentage of RCs in pure water was calculated to be similar to15%, complementing earlier work performed in this group (Lensink, M. F.; Mavri, J.; Berendsen, H. J. C. J. Comput. Chem. 1999, 20, 886), leading to a calculated rate constant of k(calc) = 3.9 x 10(-3) s(-1) (exptl: k(obs) = 2.78 x 10(-3) s(-1)). The molecular structure of the RC was examined more extensively, investigating correlations between the positions of participating molecules.