Complex formation of α-, β- and γ-cyclodextrins with 1,2,4-thiadiazole derivatives, which are structural isomers displaying an activity in the treatment of Alzheimer’s disease, was examined by the use of ¹H NMR and UV-spectroscopy. Stability constants of the complexes formed between cyclodextrins and thiadiazoles in two different buffers (pH 1.2 and 7.4) were calculated and analyzed. The temperature dependences of the stability constants were used to evaluate the enthalpy and entropy changes of complex formation. It was demonstrated that selectivity of the interactions between cyclodextrins and isometric 1,2,4-thiadiazole derivatives is determined by the size of macrocyclic cavity and relative position of the side groups in the benzene ring of the guest molecules. Higher stability of the complexes in the acidic medium (pH 1.2) in comparison with the slightly alkaline solution (pH 7.4) is caused by the important role of surface interactions.