This study was designed to unravel lipophilicity changes associated with the oxidation state of the S-atom in model compounds, drugs, and metabolites, special attention being given both to intermolecular and intramolecular effects. The methods used were experimental (potentiometry, CPC, and shake-flask techniques to measure lipophilicity, C-13-NMR spectroscopy to investigate tautomeric equilibria) and computational (quenched molecular dynamics and molecular lipophilicity potential). Simple, monofunctional model compounds were used to assess intermolecular forces, as revealed by the Delta log Poct-alk and Delta log Poct-chf parameters. Drugs and their metabolites proved to be good probes to study intramolecular effects in both neutral and anionic forms, as revealed by the difference between calculated and experimental log P-oct values (the diff(log Pexp-calc) parameter). Sulindac and its metabolites showed a normal partitioning behavior, whereas the lipophilicity of sulfinpyrazone and its metabolites was markedly affected by tautomeric and conformational equilibria