Two enantiotropic polymorphs of a tetroxoprim (TXP)-sulfametrole (SMTR) 1:1 molecular complex monohydrate and two isostructural TXP-SMTR 1:1 molecular complex solvates with methanol and ethanol were grown and studied by X-ray diffraction and thermal methods (thermogravimetric analysis and differential scanning calorimetry). Interconversion of the polymorphic hydrates is essentially an order/disorder transition involving a substituent on the TXP molecule. These hydrated phases may be described as "nearly isostructural" with the methanol and ethanol solvates. Thermal data for decomposition of the solvates were rationalized on the basis of the location and topologies of solvent crystallographic sites. Solid-state properties of two monotropic polymorphs of the unsolvated TXP-SMTR 1:1 molecular complex were also investigated and the theoretical and experimental phase diagrams of the individual components were assessed. The existence of polymorphic and pseudopolymorphic forms is determined by conformational flexibility of the TXP-SMTR bimolecular complex components, a tendency for molecular disorder in TXP, the ability of the drug complex to form intricate, highly stabilized hydrogen-bonded frameworks, and the competition between nonspecific van der Waals and specific hydrogen bond interactions.