The members of a homologous series of chiral compounds often show inconsistent enantioselectivities when separated on the same chiral stationary phase. The reasons behind this are subject to debate due to the lack of an efficient way to probe the molecular level separation mechanisms on conventional chiral stationary phases. Homochiral metal–organic frameworks (HMOFs) are a family of new porous, crystalline materials that can be used as chiral stationary phases. The regular structures of HMOFs make possible the detailed interrogation of chiral separation mechanisms through molecular modeling. In this report, molecular modeling techniques were used to study the enantioselectivities of a homologous series of chiral compounds in two different HMOFs. We demonstrate that a shift in the adsorption site is one reason for the lack of a correlation between the enantioselectivities of a homologous series of chiral compounds. In addition, we demonstrate that a smooth HMOF pore can help preserve the adsorption site and the separation mechanism, and hence achieve consistent enantioselectivity for a homologous series of chiral compounds.