The purpose of this research was to develop and optimize a sustained-release multiple unit floating system of a highly water-soluble drug, Acyclovir, using Gelucire 43/01 as lipid carrier and ethyl cellulose (EC) and methyl cellulose (MC) as release rate modifiers. Floating granules containing acyclovir were prepared by the melt granulation technique and evaluated for drug release and in vitro floating ability. A 2(3) full factorial design was used for optimization by considering the ratio of drug to Gelucire 43/01, EC, and MC as independent variables and the percentage drug released in 8h (Q(8)) and in vitro floating ability as dependent variables. The granules were evaluated for physical characterization, percentage practical yield, scanning electron microscopy, differential scanning calorimetry, FTIR, drug content, in vitro floating ability, and in vitro drug release. The floating granules had good flow properties and irregular shape with rough surface. The optimized formulation showed good floating ability and 98% drug was released in 8h. In conclusion, hydrophobic lipid, Gelucire 43/01, can be considered as an effective carrier for design of a multiunit floating drug delivery system of highly water-soluble drugs such as acyclovir.