The determination of differences in solvation free energies between related drug molecules remains an important challenge in computational drug optimization, when fast and accurate calculation of differences in binding free energy are required. In this study, we have evaluated the performance of five commonly used polarized continuum model (PCM) methodologies in the determination of solvation free energies for 53 typical alcohol and alkane small molecules. In addition, the performance of these PCM methods, of a thermodynamic integration (TI) protocol and of the Poisson–Boltzmann (PB) and generalized Born (GB) methods, were tested in the determination of solvation free energies changes for 28 common alkane-alcohol transformations, by the substitution of an hydrogen atom for a hydroxyl substituent. The results show that the solvation model D (SMD) performs better among the PCM-based approaches in estimating solvation free energies for alcohol molecules, and solvation free energy changes for alkane-alcohol transformations, with an average error below 1 kcal/mol for both quantities. However, for the determination of solvation free energy changes on alkane-alcohol transformation, PB and TI yielded better results. TI was particularly accurate in the treatment of hydroxyl groups additions to aromatic rings (0.53 kcal/mol), a common transformation when optimizing drug-binding in computer-aided drug design. © 2013 Wiley Periodicals, Inc.