The objects of this work are novel 1,2,4-thiadiazole derivatives which were recently synthesized and proposed for the treatment of Alzheimer’s disease [1,2]. Solubility of these compounds is not high and lies in the range of 10-4–10-3 M. Inclusion complex formation with cyclodextrins is known as one of the methods used to improve the aqueous solubility of pharmacologically active compounds [3,4]. Cyclodextrins (CDs) are cyclic oligosaccharides consisting of glucopyranose units linked by α-(1,4)-glycosidic bonds. Owing to the sufficient solubilizing capacity of CDs they are widely used in pharmacy for preparation of different dosage forms of poorly soluble compounds [3,4]. Solubilizing effect of CDs is based on their ability to inclusion complex formation. Hydrophobic cavity of CDs can accommodate drug molecule, and hydrophilic exterior of CDs provides the dissolution of inclusion complexes in aqueous media. Therefore, investigation of complex formation of CDs with drugs is of practical importance. In this connection, complex formation of native and modified CDs with 1,2,4-thiadiazole derivatives in phosphate buffer (pH 7.4) was studied by isothermal titration calorimetry and 1H NMR spectroscopy at 298.15 K. It was found that more stable inclusion complexes are formed with β-CD and γ-CD and they are typically enthalpy-entropy stabilized. On other hand, van der Walls interactions and hydrogen bonding determine the negative values of ΔcH and TΔcS obtained for complex formation of 1,2,4- thiadiazole derivatives with α-CD. Binding mode of CDs with 1,2,4thiadiazole derivatives was proposed on the basis of 1D and 2D 1H NMR (ROESY) experiments The impact of CDs and thiadiazole structure on thermodynamics and binding mode was analyzed.