Understanding the origin of the regioselectivity of inositol derivatives is essential to the synthetic design of these biologically important molecules. We have undertaken a study of the regioselectivities displayed by the myo-inositol derivatives toward electrophiles using various levels of quantum mechanical calculation : Hartree-Fock (HF) theory, Moller-Plesset second-order perturbation (MP2) theory, density functional theory (DFT), and self-consistent reaction field (SCRF) theory. Various basis sets were also tested. The systems investigated here are 1,2:4,5-di-O-methylidene-myo-inositol and its probable intermediates (deprotonated and sodium-chelated species). In experiments the O3 position was the major site for derivatization of the molecule. However, the MP2 and DFT results could not explain the experiments. Taking into account that the myoinositol derivatives were highly insoluble with the exception of some polar solvents, we performed the SCRF calculations using the dielectric constant (epsilon) of 40. These results show agreements with the experimental results. In the presence of solvents with lame dielectric constants, the regioselectivity in favor of the O3 position is not only due to reduced Coulombic repulsion between the deprotonated oxygen and its vicinal oxygen but also due to reduced anisotropicity of the polarization from Na toward two vicinal oxygens.