Three known and one new unsolvated polymorphic phase A, B, C, and D of diflunisal were grown and studied by X-ray diffraction, IR-spectroscopy, solution calorimetry, and DSC methods. Their structures are compared to another previously described modification E.1 Relationships were studied between O-H and C=O stretching frequencies and between C=O stretching frequency and the molecular volume of diflunisal in the respective crystal lattice. According to regularities found it was proposed that the existence of polymorphic forms is determined by conformational flexibility of the molecule, ability to create inter- and intramolecular hydrogen bonds and the competition between nonspecific van der Waals and specific hydrogen bond interactions. The volume per molecule in the crystal lattice are: A < B < C < E < D (XRD Ito method). Forms A and C are enantiotropic with a difference in crystal lattice energies of 1.9 +/- 0.5 kJ.mol( - 1). Modifications B, C, D, and A, B, D are monotropic. Based on solution enthalpies, absolute values of the lattice showed only small differences ("isoenergetic" polymorphs), and can be arranged in increasing order: B approximately A < C < D.