beta-Lactam antibiotics tend to undergo self-association in hydrophilic organic solvents, which leads to a strong dependence of their experimentally observable log P values on the partitioning conditions. As a result, most of the earlier obtained log P values for beta-lactam antibiotics cannot be applied as a common hydrophobicity measure, but they proved to be linearly related to each other and to a large body of reversed-phase chromatographic data. The retention of cephalosporins on reversed-phase liquid chromatographic columns is complicated by silanophilic interactions. However, under elution conditions that eliminate these silanophilic interactions, good correlations with log P data are observed, and a unified hydrophobicity scale for 90 penicillin and cephalosporin compounds could be evaluated. The Hansch and Leo additive scheme was shown to be valid for the calculation of hydrophobicities for penicillin and cephalosporin C-6(7) substituents, but it failed when applied to the prediction of cephalosporin C-3-substituent hydrophobicities. The hydrophobic increments for the sixteen most common cephalosporin C-3-substituents were empirically evaluated from literature data, and a simple equation was derived for an overall beta-lactam antibiotic hydrophobicity calculation. The proposed scale is valid for predicting the partitioning of most beta-lactam antibiotics in both hydrophilic and lipophilic organic-water systems, although it should be used with caution when applied to antibiotics containing additionally charged side-chains.