Zero-point energies (ZPE) and isotope effects, induced by intermolecular, noncovalent vibrations, are computed and tested by experimental data. The ZPE differences of H- and D-complexes of water with hydrogen, methane, and water molecules are about 100–300 cal/mol; they result to isotope effects IE of 1.20–1.70. Semi-ionic bonds between metal ions and water ligands in M(H2O) 2+6 complexes are much stronger; their ZPEs are about 12–14 kcal/mol per molecule and result to IE of 1.9–2.1 at 300 K. Protonated (deuterated) water and biwater exhibit the largest ZPE differences and isotope effects; the latter are 25–28 and 12–13 for water and biwater, respectively. Noncovalent IEs contribute markedly into the experimentally measured effects and explain many anomalous and even magic properties of the effects, such as the dependence of IE on the solvents and on the presence of the third substances, enormously large isotope effects at the mild conditions, the difference between IEs measured in the reactions of individual protiated and deuterated compounds and those measured in their mixture. Noncovalent IEs are not negligible and should be taken into account to make correct and substantiated conclusions on the reaction mechanisms. The kinetic equations are derived for the total isotope effects, which include noncovalent IEs as additive factors.