Metal-organic frameworks (MOFs) are promising adsorbents for hydrogen storage. Density functional theory and second-order Møller−Plesset perturbation theory (MP2) using the TURBOMOLE program package are used to calculate the interaction energies between H₂ and individual structural elements of the MOF-5 framework. The strongest interaction, ΔH₇₇ = −7.1 kJ/mol, is found for the α-site of the OZn₄(O₂Ph)₆ nodes. We show that dispersion interactions and zero-point vibrational energies must be taken into account. Comparison of calculations done under periodic boundary conditions for the complete structure with those done for finite models cut from the MOF-5 framework shows that the interactions with H₂ originate mainly from the local environment around the adsorption site. When used within a Multi-Langmuir model, the MP2 results reproduce measured adsorption isotherms (the predicted amount is 6 wt % at 77 K and 40 bar) if we assume that the H₂ molecules preserve their rotational degrees of freedom in the adsorbed state. This allows to discriminate between different isotherms measured for different MOF-5 samples and to reliably predict isotherms for new MOF structures.