Abstract Clotrimazole is a lipophilic drug of an antimycotic action used both locally and systemically. Improvement of solubility and release rate of the clotrimazole is therefore essential for a rapid antimycotic activity. Hence, the effect of cyclodextrins (CDs) on the physicochemical properties and antimycotic activity of clotrimazole was studied. Inclusion complexation of clotrimazole with α-, β- and DM- β-CD was assessed by solubility method, microbiological assay, differential scanning calorimetry (DSC) and powder X-ray diffractometry. The solubility of clotrimazole was increased markedly with DM- β-CD, among the studied CDs, showing A N-type phase solubility diagram. The antimycotic activity of clotrimazole against Candida albicans ( C. albicans) was improved as measured for the solubilized amounts of clotrimazole taken from the phase solubility diagrams with CDs. DSC curve of coevaporate of clotrimazole with DM- β-CD showed almost no peak in the transition region of clotrimazole which could be attributed to the complex formation. Moreover, powder X-ray diffraction pattern of coevaporate of clotrimazole with DM- β-CD gave new crystalline diffraction pattern which confirmed the DSC results of inclusion complexation between clotrimazole and DM- β-CD. The coevaporates of clotrimazole with CDs showed superior antimycotic activity against C. albicans than the physical mixtures and drug alone, respectively. The largest inhibition zone of growth of C. albicans was obtained in the case of inclusion complex of clotrimazole with DM- β-CD. The coevaporate of clotrimazole with DM- β-CD showed higher dissolution rate in good correlation with the solubility data, and these reflect the higher antimycotic activity by rapid diffusion through agar medium. Both physical mixture and inclusion complex of clotrimazole with DM- β-CD were formulated as effervescent vaginal tablets; they found to possess an excellent antimycotic activity.