The distributions of Brönsted acidic protons and their acid strengths in zeolite H-MCM-22 have been characterized by density functional theory (DFT) calculations as well as magic angle spinning (MAS) NMR experiments. The embedded scheme (ONIOM) that combines the quantum mechanical (QM) description of active sites and semiempirical AM1 treatment of the neighboring environment was applied to predict the aluminum substitution mechanism and proton affinity (PA), as well as adsorption behaviors of acetone and trimethylphosphine oxide (TMPO) onto the zeolite. Our theoretical results indicate that the Al substitution takes place in the order of Al1-OH-Si2 > Al8-OH-Si8 > Al5-OH-Si7. The DFT theoretical and NMR experimental results suggest that the acid strength of the three Brönsted acid sites in H-MCM-22 zeolite is slightly lower than that of H-ZSM-5 zeolite and the accessible Brönsted acidic protons most likely reside in both the supercages (at the Al8-OH-Si8 and Al1-OH-Si2 sites) and external surface pocket (at the Al8-OH-Si8 site) rather than in the sinusoidal channels (Al5-OH-Si7), with the Al1-OH-Si2 site having the strongest acid strength (as probed by TMPO). This may partially explain the special selectivity of acid-catalyzed reactions occurring inside the channels of H-MCM-22 zeolite.