Lipophilicity is a fundamental property to characterize the structure and function of proteins, motivating the development of lipophilicity scales. We report a versatile strategy to derive a pH-adapted scale that relies on theoretical estimates of distribution coefficients from conformational ensembles of amino acids. This is accomplished by using an accurately parametrized version of the IEFPCM/MST continuum solvation model as an effective way to describe the partitioning between n-octanol and water, in conjunction with a formalism that combines partition coefficients of neutral and ionic species of residues and the corresponding p Ka values of ionizable groups. Two weighting schemes are considered to derive solvent-like and protein-like scales, which have been calibrated by comparison with other experimental scales developed in different chemical/biological environments and pH conditions as well as by examining properties such as the retention time of small peptides and the recognition of antigenic peptides. A straightforward extension to nonstandard residues is enabled by this efficient methodological strategy.