Prediction of osmotic pressure controlled flux decline during ultrafiltration requires an accurate theoretical determination of the osmotic pressure of macromolecular solutions at high concentrations, where non-van’t Hoffian contribution becomes significant. A model for osmotic pressure determination is used which is based on facile measurements of surface properties of solutes. The knowledge of the apolar and polar (acid-base) interaction energies of polymeric molecules in water leads to the determination of the Flory-Huggins interaction parameter. Estimates of the interaction parameter as a function of the solute concentration lead to the direct theoretical prediction of osmotic pressure of various macromolecular solutions up to high concentrations approaching the gel limit. The osmotic pressure of the macromolecular solutions thus determined is used to predict the osmotic pressure controlled flux decline. A model is developed by solving the coupled velocity and concentration fields to predict flux during unstirred, stirred, and parallel plate ultrafiltration. For all of these configurations, experimental flux decline and limiting nux data are obtained for PEG and Dextran under various operating conditions. The model predictions are compared to experimental nux data which show a remarkable agreement even in the absence of any adjustable parameter in the model. Results help in the identification and quantification of the solute-solute interactions as a factor affecting permeate flux during osmotic pressure controlled flux decline. The theory of osmotic pressure controlled ultrafiltration can also be used as an efficient tool for osmometry.