A new chromatographic method to determine the octanol–water partition coefficient (logP o/w ) of organic substances is proposed in this paper. This method is based on a previously reported model that relates the retention factor in reversed-phase liquid chromatography with solute (p), mobile phase (PmN) and stationary phase (PsN) polarity parameters: logk=(logk)0+p(PmN−PsN). PmN values are calculated through expressions that depend only on the organic solvent fraction in the mobile phase. (logk) 0 and PsN parameters are characteristic of the chromatographic system and are determined from the retention of a selected set of 12 compounds. Then, the p value of a solute determined in a properly characterized system is easily derived from the retention factor data. Solute p values are slightly dependent on the chromatographic system but they are linearly related to those obtained in the reference system (Spherisorb ODS-2 column and acetonitrile as organic modifier). Therefore, they can be easily transferred from any experimental system to the reference one. A Quantitative Structure–Property Relationship study reveals that the p parameter in the reference chromatographic system depends, mainly, on the hydrophobicity of the compound, expressed as the n-octanol/water partition coefficient (logP o/w ), and five additional structural descriptors which can be easily calculated through the CODESSA program from the chemical structure of the solute. In this work the p descriptors of a wide set of structurally different organic compounds have been determined in several chromatographic systems and transferred to the reference one from these and the CODESSA structural parameters. The logP o/w values have been determined. The obtained values agree with those determined from classical experimental techniques and validate the new method as a useful tool to determine the hydrophobicity of a wide variety of compounds in a broad logP o/w range.