The molecular parameters and intermolecular forces controlling partition coefficients (P) in the 1,2-dichloroethane (DCE)–water system have been studied. A set of 44 solutes was selected to allow a regular and broad exploration of property spaces. Log Pdce values were measured by the shake-flask method, centrifugal partition chromatography, and/or the pH-metric method. Linear solvation Gibbs-energy relationship (LSER) analyses showed that log Pdce values are controlled by the molecular volume of the solutes and by their H-bonding donor acidity and acceptor basicity, with a contribution from the latter parameters significantly greater than in n-octanol–water partition coefficients. The DCE–water system appears as a promising alternative to the alkane–water system for obtaining partition coefficients of interest in structure–permeation relationship studies.