In order to explore the nature of hydrogen-bonding with isotope effect, we have developed the multi-component molecular orbital (MC_MO) method, which takes into account the quantum effect of proton and deuteron, beyond Born-Oppenheimer approximation. In the case of H₂, HD, and D₂ molecules, we have clearly demonstrated that the difference of charge distributions between proton and deuteron reflects the electronic structure and bond distance (see Figure 1). This MC_MO method is a powerful tool to study the geometrical and kinetic isotope effects for various chemical phenomena, such as the hydrogen-absorbing metallic nanoparticle, C-H...O type hydrogen-bonding, and hydrogen (proton) abstraction reaction.