The adsorption of polar water and methanol vapors on the meso- and microporous metal–organic frameworks (MOFs) MIL-100(Cr) and MIL-101(Cr) has been studied by a combined experimental and simulation approach. The computational effort for these MOFs with large unit cells was reduced by using primitive unit cells that were 4 times smaller. Our results demonstrate that both adsorbate–adsorbent and adsorbate–adsorbate interactions control the adsorption process. At low loadings, before all coordinatively unsaturated chromium sites are occupied, the MOF structure determines the shape of the isotherm, and the molecular model for the polar sorbate is less important. A clear difference was found between fully fluorinated and hydroxylated MIL-101 structures for both methanol and water, demonstrating that partial charges on Cr drive the initial shape of the isotherm. At higher loadings, adsorbate–adsorbate interactions become much more important, and the choice of the water model, in particular, is crucial for the agreement between experimental and simulation results. The simplest SPC/E model reproduces the experimental results with the best accuracy, in contrast to more advanced models such as TIP5PEw, which can be explained by the slightly stronger Coulombic interactions predicted by the former. For methanol, the general TraPPE force field performs well. A composite type IV isotherm for methanol and a composite type V isotherm for water, according to the IUPAC classification, were found. The heats of adsorption are in line with these conclusions. To the best of our knowledge, this effect of the sorbate model has not been observed in adsorption in microporous materials, and it highlights the complexity behind molecular simulations in periodic mesostructured materials.