The use of the conductor-like screening with segment activity coefficient (COSMO-SAC) model to predict octanol-water partition coefficients (log K-O/W) for selected nanoscale building blocks (NBBs) has been evaluated. COSMO calculations have been performed using charge density information obtained from density functional theory calculations of the compounds that, in turn, provide input data that allow the calculation of the activity coefficient in the COSMO-SAC model. The NBBs of interest in this study are C-60, the hydrogen functionalized polyhedral oligomeric silsesquioxane Si8O12H8 (H-POSS), and their functionalized variants C-60(OH)(32), Si8O12F8 (F-POSS), and Si8O12(OH)(8) (OH-POSS). It is found that COSMO-SAC, while being unable to accurately predict the solubility of very hydrophobic compounds in water, can quickly and efficiently provide qualitative estimates of log K-O/W for the selected solutes. The COSMO-SAC estimation of log K-O/W for C-60 is 6.79, which is consistent with the experimentally reported value and reflects the general consensus that C-60 is strongly hydrophobic. No partitioning data are available for H-POSS or the functionalized NBBs studied. In this work, COSMO-SAC calculations on these particles indicate shifts toward water partitioning for C-60(OH)(32), F-POSS, and OH-POSS relative to their respective base particles (C-60 and H-POSS). These shifts in water solubility are consistent with the calculation of the Gibbs free energy of hydration for each particle using molecular dynamics simulations and thermodynamic integration.