A general multi-scale framework for multi-component, multi-phase equilibrium flash calculations, which uses information at the molecular and bulk fluid length scales, is described. The multi-scale Gibbs-Helmholtz constrained (GHC) EOS approach of Lucia (2010) is extended to include the use of (1) coarse grained NTP Monte Carlo simulations to gather pure component internal energies of departure, (2) a new linear mixing rule for internal energies of departure for mixtures, (3) a novel expression for partial fugacity coefficients for the GHC EOS, and (4) a novel flash algorithm that uses complex-valued compressibility factors and densities to assist in phase existence determination. Many numerical results for mixtures of CO2-water, NaCl-water, and CO2-NaCl-water are used to show that the GHC EOS flash approach is superior to all other approaches currently available. Many geometric illustrations are presented to elucidate key concepts and many experimental validations are used to substantiate claims of superiority. (C) 2011 Elsevier Ltd. All rights reserved.