Diflorasone diacetate, a steroid anti-inflammatory drug (marketed as Diacort or Florone by Pfizer) and used in the treatment of skin disorders, can be prepared as anhydrous form, DD1 (as deposited in the US pharmacopoeia), or as a monohydrated phase, DDW. Heating the DDW form above 90 degrees C, a mixture of DD1 and of a new anhydrous polymorph, DD2 is obtained. Further heating of this mixture, or of pure DD1, up to 230 degrees C (only a few degrees before melting!), generates an elusive anhydrous DD3 polymorph. Their crystal structures, determined uniquely from laboratory powder diffraction data, show the isomorphous character of the DDW and DD1 forms, while the DD2 and DD3 polymorphs crystallize with markedly different unit cells. Crystals of the DD1, DD2 and DDW forms are orthorhombic, P2(1)2(1)2(1), a=29.386(1)A; b=10.4310(9)A, c=8.1422(7)A, V=2495.8(3)A(3) for DD1; a=15.2639(10)A; b=11.7506(7)A, c=13.8931(11)A, V=2491.9(3)A(3) for DD2; a=30.311(2)A; b=10.6150(9)A, c=7.9337(7)A, V=2552.7(4)A(3) for DDW; while the lattice parameters for the monoclinic P2(1)DD3 species are a=11.5276(10)A; b=13.8135(11)A, c=7.8973(7)A, beta=103.053(6) degrees , V=1225.0(2)A(3). These compounds have also been fully characterized by thermo analytical methods, as well by (13)C, (19)F, and (1)H NMR spectroscopy.