The bimolecular nucleophilic substitution reaction of CCl4 and OH- in aqueous solution was investigated on the basis of a combined quantum mechanical and molecular mechanics method. A multilayered representation approach is employed to achieve high accuracy results at the CCSD(T) level of theory. The potential of mean force calculations at the DFT level and CCSD(T) level of theory yield reaction barrier heights of 22.7 and 27.9 kcal/mol, respectively. Both the solvation effects and the solvent-induced polarization effect have significant contributions to the reaction energetics, for example, the solvation effect raises the saddle point by 10.6 kcal/mol. The calculated rate constant coefficient is 8.6 x 10(-28) cm(3) molecule(-1) s(-1) at the standard state condition, which is about 17 orders magnitude smaller than that in the gas phase. Among the four chloromethanes (CH3Cl, CH2Cl2, CHCl3, and CCl4), CCl4 has the lowest free energy activation barrier for the reaction with OH- in aqueous solution, confirming the trend that substitution of Cl by H in chloromethanes diminishes the reactivity.