The objective of this study was to unravel the structural properties responsible for the partitioning of solutes in o-nitrophenyl octyl ether (o-NPOE)/H2O, a new solvent system for the determination of the partition coefficients of ions. A set of 88 compounds (including drugs) was selected to allow a regular and broad distribution of property spaces. Partition coefficients in o-NPOE/H2O (log P-npoe)were measured by the shake-flask or the potentiometric method. Linear solvation free-energy relationship (LSER) analyses showed that Van der Waals volume, H-bond-acceptor basicity, and H-bond-donor acidity are the three molecular descriptors of solutes determining their log P-npoc values. The partitioning mechanism of the investigated compounds in oNPOE/H2O is controlled by the same structural properties as it is in 1,2-dichloroethane (DCE)/H2O. Deltalog Values (difference between log P-oct and log P-npoe) express mainly dipolarity/polarizability and H-bond-donor acidity. The solvent o-NPOE is shown to be a good candidate to replace DCE in measurements of lipophilicity