An extended and generalized Flory-Huggins model for calculating the heats of mixing and predicting the phase stability and spinodal diagrams of binary polymer-polymer mixtures is presented. In this model, the interaction parameter is considered to be a function of both temperature and composition. It is qualitatively shown that the proposed model can calculate the heats-of-mixing curves containing exothermic, endothermic, and S-shaped or sigmoidal types and predict the spinodals, including the upper and lower critical solution temperatures, and closed-loop miscibility regions. Using experimental results of analog calorimetry for four polymer mixtures of polystyrene/poly(vinyl chloride) (PS/PVC), polycarbonate (PC)/poly(ethylene adipate) (PEA), polystyrene/poly(vinyl acetate) (PS/PVAc), and ethylene vinyl acetate copolymer (EVA Co)/chlorinated polyethylene (CPE), the capabilities of the proposed functionality for the interaction parameter was studied. It is shown that this function can be used satisfactorily for the heat-of-mixing calculations and phase-behavior predictions.