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 Pnpoe) 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 Pnpoe values. The partitioning mechanism of the investigated compounds in o‐NPOE/H2O is controlled by the same structural properties as it is in 1,2‐dichloroethane (DCE)/H2O. Δlog Poct−npoe Values (difference between log Poct and log Pnpoe) 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.