Molecular lipophilicity can be expressed by log P or more conveniently by log kw, determined by the so-called "shake-flask" (SF) technique or by reversed-phase high-performance liquid chromatography (RP-HPLC), respectively. In the present study, the lipophilicity of a large set of solutes was measured by RP-HPLC on a silanol-deactivated octylsilane (OS) reversed phase, namely Inertsil OS (IN). IN lipophilicity parameters were found to be fairly well correlated with log P. A Linear Solvation Energy Relationship (LSER) study revealed that cavity term (modeled by intrinsic molar volume, V1) and hydrogen-bond acceptor capacity (modeled by the solvatochromic parameter beta) of solutes are the most important factors affecting retention on Inertsil OS. The comparison of LSER model for retention on Inertsil with those obtained for two other silanol-deactivated OS stationary phases, namely Deltabond OS and RP Select B, shows that alpha (H-bond donor activity of solutes) can be used as a parameter able to discriminate the behaviour of different stationary phases. QSAR studies indicated that lipophilicity parameters determined on silanol-deactivated OS phases have potential in medicinal chemistry applications.