A predictive approach for calculating the binary interaction parameters ( ij) of the nonrandom two liquid (NRTL) local composition model is developed, combining molecular simulations with the two-fluid theory. The binary interaction parameters are determined for the following three sets of model binary mixtures: water+methanol, methanol+methyl acrylate, and water+methyl acrylate. For each binary mixture, the interaction parameters are expressed in terms of molecular size and strength of interactions, which are in turn, calculated from molecular simulations. We show that the binary interaction parameters determined from simulations are in qualitative agreement with those estimated from regressing experimental data. The major factors that determine the binary interaction parameters are outlined based on simple thermodynamic arguments for each mixture. (c) 2018 American Institute of Chemical Engineers AIChE J, 64: 2758-2769, 2018