Hollow buoyant microspheres of Zidovudine with Eudragit RS100 were successfully prepared by the oil in water emulsion solvent diffusion technique with better percentage yield. The problem associated with less Entrapment efficiency of drug in microspheres was overcome by modification of aqueous phase. The concentration of polymer also affected Buoyancy of microspheres in same proportionality. All the formulation exhibited excellent to good flow properties when evaluated for micromeritic properties. The drug release pattern was greatly affected by the concentration of polymer. The release was slower in the high polymer concentration formulation as compare to low polymer concentration formulations. The drug release of various formulations of microsphere was through Zero order model and drug release mechanism was through Non-Fickian case-II transport mechanism.