The lipophilicities of 22 selected sunscreens, preservatives, and vitamins used in topical skin products were measured by thin-layer chromatography. Lipophilicity was calculated in silico from the sunscreen molecular structures and compared to the experimental octanol/water partition coefficients found in the literature. The retention of the compounds was investigated on an RP-18 stationary phase with mobile phases consisting of water and one of six organic modifiers (dioxane, tetrahydrofuran, acetone, acetonitrile, methanol, and dimethylformamide) at different concentrations. The theoretical lipophilicities were calculated by several computational algorithms and the results of these calculations were compared using cluster analysis. The results showed that two out of the six investigated organic modifiers (dioxane and acetone) may be used to estimate the octanol/water partition coefficients of highly lipophilic compounds having lipophilicities that cannot be measured directly by the shake-flask method.