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This study was carried out with the aim to optimize the pharmacological profile of gliquidone (GLI)—a poorly bioavailable hypoglycaemic agent sparingly soluble in water- through complexation with cyclodextrins. In order to increase the apparent solubility of GLI, two cyclodextrins, namely β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD), were tested. The effect of cyclodextrin addition on the aqueous solubility of GLI was evaluated by the phase solubility method at different pH values. The amount of GLI in solution increased upon CD addition according to A type plots. The aqueous solubility of GLI was enhanced more at higher pH values and using HPβCD. On the basis of its performance, HPβCD was selected as host to prepare GLI oral formulations. GLI/HPβCD solid systems were prepared at 1:2 molar ratio by co-grinding, spray-drying and freeze-drying and characterized by DSC, FTIR and X-ray powder diffractometry. Powders were amorphous and showed an improved dissolution rate in comparison with GLI. GLI/HPβCD co-ground and freeze-dried products were the most interesting systems, since they dissolved 62 and 94% of total drug after 15 min, respectively. The hypoglycaemic effect of the most rapidly dissolving binary systems was evaluated after oral administration in fasted rats by measuring plasma glucose level in the time interval 0.5–36 h and compared to free GLI. Our findings indicate that cyclodextrin-containing formulations not only provide an onset of hypoglycaemic effect faster than GLI, but also enhance significantly the pharmacological effect due to improved biopharmaceutics. The association GLI/HPβCD allows a reduction of the oral dose and is expected to provide a better control over drug side effects, contributing to improve safety and efficacy of GLI. [Copyright &y& Elsevier]