The reliability of the two-layered ONIOM (our own N-layered molecular orbital + molecular mechanics) method was examined for the investigation of the S(N)2 reaction pathway (reactants, reactant complexes, transition states, product complexes, and products) between CH3Cl and an OH- ion in microsolvation clusters with one or two water molecules. Only the solute part, CH3Cl and OH-, was treated at a high level of molecular orbital (MO) theory, and all solvent water molecules were treated at a low MO level. The ONIOM calculation at the MP2 (Moller-Plesset second order perturbation)/aug-cc-pVDZ (augmented correlation-consistent polarized valence double-zeta basis set) level of theory as the high level coupled with the B3LYP (Becke 3 parameter-Lee-Yag-Parr)/6-31 + G(d) as the low level was found to reasonably reproduce the "target" geometries at the MP2/aug-cc-pVDZ level of theory. The energetics can be further improved to an average absolute error of <1.0 kcal/mol per solvent water molecule relative to the target CCSD(T) (coupled cluster singles and doubles with triples by perturbation)/aug-cc-pVDZ level by using the ONIOM method in which the high level was CCSD(T)/aug-cc-pVDZ level with the low level of MP2/aug-cc-pVDZ. The present results indicate that the ONIOM method would be a powerful tool for obtaining reliable geometries and energetics for chemical reactions in larger microsolvated clusters with a fraction of cost of the full high level calculation, when an appropriate combination of high and low level methods is used. The importance of a careful test is emphasized.