The purpose of this study was to investigate the influence of hypolipidemic atorvastatin calcium (ATC) floating microspheres on the LDL and HDL levels in rabbit blood. ATC Floating microspheres were prepared via emulsion solvent evaporation method using Eudragit S100 as a 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 investigated. 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 release % which was 66% after 8 h. Furthermore, F5 significantly decreased the blood LDL and increased HDL levels in comparison to the market drug (ATOR ®) and it succeeded in lowering the blood total cholesterol level of rabbits by 74.42%.