A general methodology involving semi-batch experimental design is proposed in order to determine the volumetric standard states as well as homotactic and heterotactic volumetric solute-solute interaction coefficients from the associated quaternary solutions alone. The densities of quaternary aqueous solutions consisting of three alcohol solutes, e.g. methanol, ethanol, and I-propanol, in the range of concentrations 0.0000 < x(solute-i) < 0.0093 at 298.15 K and 0.1013MPa were measured in order to demonstrate the utility of this methodology. The volumetric standard states as well as the interaction coefficients were determined from combined use of a multivariate response surface model together with the McMillan-Mayer formalism and a 3rd-order virial expansion, without relying on either pure component properties or binary/ternary solution information. Since no external measurements are admitted, additional sources of experimentally induced error are eliminated, and the associated numerical sensitivity of the excess volumetric equations is more appropriately treated. The volumes of interaction reveal that hydrophobic-hydrophobic interactions predominate. All homotactic and heterotactic interaction coefficients are negative and their magnitudes increase with increasing alcohol chain length. The coefficients obtained from quaternary-solution multivariate analysis are in good agreement with separate binary and ternary measurements reported in the literature. Such a general approach should provide new opportunities for the understanding of molecular recognition processes in complex solutions. (c) 2007 Elsevier Ltd. All rights reserved.