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Halogenation is an indispensable method in the structural modification of lead compounds. It is known to increase lipophilicity and is hence used to improve membrane permeability and thus bioavailability. In this study, we compare the water solubility (logS) of organohalogen compounds and their non-halogenated parent compounds using the molecular matched pair (MMP) analysis method. Unexpectedly, 19.9% of the compounds increased their water solubility upon halogenation. Iodination was observed to have the greatest effect on solubility, followed by chlorination, bromination, and fluorination. Introducing amino, hydroxyl and carboxyl groups into organohalogens improves their aqueous solubilities, whereas introducing a trifluoromethyl group has the opposite effect. According to our quantum chemical calculations, the increased water solubility upon halogenation is, at least partially, attributed to an increased polarity and polarizability. These results improve our understanding of the influence of halogenation on bioactivity.