Ezetimibe (EZT) is a cholesterol lowering agent that is characterized by a low aqueous solubility resulting in unpredictable dissolution and bioavailability. Hence, the enhancement of dissolution is a way to improve its bioavailability. Freeze-drying of EZT with Soluplus was the approach used in this study. Different ratios of EZT: Soluplus were prepared using freeze-drying or using a mortar and pestle (physical mixing). All of the prepared ratios were characterized using Differential Scanning Calorimetry (DSC), Fourier transform infrared spectroscopty (FTIR), X-ray diffraction (XRD) and Scanning electtrom microscopy (SEM to make sure there was no interaction between the drug and polymer. An in-vitro release study was performed, and the best ratio with the highest release was chosen for in-vivo release in hypercholesterolemic rats. The cholesterol level was measured before as well as 7 and 14 days after receiving EZT by oral gavage using three groups of rats; the first group received pure EZT, the second group received freeze-dried EZT with Soluplus and the third group was the control group. Blood samples were also withdrawn from these three groups of rats. It was found that the freeze-dried EZT with Soluplus gave the highest protection from cholesterol and the highest plasma concentration compared to pure EZT. Additionally, it was found that the EZT:Soluplus 1:5 ratio had higher dissolution resulting in greater absorption of EZT, and hence, it had greater bioavailability and a higher capability of lowering the cholesterol to its normal level. (C) 2017 Elsevier B.V. All rights reserved.