The objective of the study was to develop a stomach-specific drug delivery system for controlled release of Clarithromycin for eradication of Helicobacter pylori (H. pylori). Floating Microspheres of Clarithromycin (FMC) were prepared by Solvent Evaporation Technique using ethyl cellulose as a polymer. The prepared microspheres were subjected to evaluation for particle size, incorporation efficiency, in vitro buoyancy, in vitro drug release characteristics and stability studies. These microspheres showed good buoyancy. The formulation variables like polymer concentration and drug concentration influenced the in vitro drug release significantly in simulated gastric fluid (pH. 2.0). It was also noted that the required amount of Clarithromycin for eradication of H. pylori was significantly less in FMC than from corresponding Clarithromycin suspension. About 82% of the prepared microspheres floated in hydrochloric acid buffer solution for 12h. 71% of the Clarithromycin contained in the microspheres were released within 12 h in a sustained manner. These results suggest that FMC will be a promising drug delivery system for the treatment of H. pylori infection.