This paper presents a methodology to predict PVC plasticization using molecular simulation of binary interaction between molecules in three kinds of pairs: plasticizer-plasticizer, PVC-PVC, and PVC-plasticizer. The plasticization prediction is based on three complementary criteria calculated from thermodynamic data, obtained from molecular simulation. The methodology was applied to a group of commercial products and to potential new plasticizers, specifically glycerol and isosorbide esters. The predictions were contrasted with the experimental performance evaluated with several tests usually employed in PVC industry. The methodology can be used to test molecular structures and to reduce the experimental work necessary for the evaluation of new PVC plasticizers.