The purpose of this study was to investigate the influence of hypolipidemic atorvastatin calcium (ATC) floating microspheres on the LDL and HDL level in rabbit blood. Floating microspheres-loaded ATC were prepared via emulsion solvent evaporation method using Eudragit S100 as polymer. The effect of certain variables including drug: polymer ratio, stirring rate, emulsifier concentration and internal: external phase volume ratio on the floating microspheres formulations were performed. Evaluation of floating microspheres was done using particle size analysis, percentage yield, in-vitro buoyancy, entrapment efficiency determination, optical microscopy, in-vitro drug release studies, Thermal analysis (DSC) and Fourier transform infrared spectroscopy (FTIR). The prepared microspheres showed a good floating ability. The Floating microspheres formulation No (F5) revealed the highest %drug released (66%) after 8 h. Furthermore, F5 significantly decreased the blood LDL and increased HDL in comparison with the market drug (ATOR ®) and it succeeded in lowering the rabbit's blood total cholesterol level by 74.42%.