In order to determine the impact of different substituents and their positions on intermolecular interactions and ultimately on the crystal packing, unsubstituted N-phenyl-2-phthalimidoethanesulfonamide, C16H14N2O4S, (I), and the N-(4-nitrophenyl)-, C16H13N3O6S, (II), N-(4-methoxyphenyl)-, C16H16N3O6S, (III), and N-(2-ethylphenyl)-, as the monohydrate, C18H18N2O4S center dot H2O, (IV), derivatives have been characterized by single-crystal X-ray crystallography. Sulfonamides (I) and (II) have triclinic crystal systems, while (III) and (IV) are monoclinic. Although the molecules differ from each other only with respect to small substituents and their positions, they crystallized in different space groups as a result of differing intra-and intermolecular hydrogen-bond interactions. The structures of (I), (II) and (III) are stabilized by intermolecular N-H center dot center dot center dot O and C-H center dot center dot center dot O hydrogen bonds, while that of (IV) is stabilized by intermolecular O-H center dot center dot center dot O and C-H center dot center dot center dot O hydrogen bonds. All four structures are of interest with respect to their biological activities and have been studied as part of a program to develop anticonvulsant drugs for the treatment of epilepsy.