Introduction: Helicobacter pylori infection is strongly associated with chronic gastritis and duodenal ulcers which can benefit from gastroretentive delivery of clarithromycin. Objectives: The objective of this study was to investigate mucoadhesive microspheres of the antibiotic – resin complex for gastro-retention, thereby increasing the local effective concentrations of clarithromycin. Methods: Clarithromycin-resin complex granules were coated with the mucoadhesive polymers, Carbopol 934 and Polycarbophil in different ratios of 1:1, 1:2, 1:3 and 1:4 by solvent evaporation method. Prepared microspheres were subjected to characterization for particle size and shape, drug content, in vitro mucoadhesion, in vitro drug release and in vivo gastric residence time in albino rats. Results and Discussion: Particle sizes of the microspheres were found to be in the range of 83 μm-87μm. Scanning electron microscopic images of the formulation showed spherical particles with almost smooth surface morphology for carbopol microspheres. Formulations with both polymers showed mucoadhesion for a period of more than 6 hr. In vitro drug release using the USP dissolution test apparatus appeared to follow first order kinetics. Fluorescence imaging of histo-pathological slides of rats gastric and intestinal mucosa reveal that gastric residence time was found to be longer than 6 h for carbopol microspheres and at least 4 h in the case of polycarbophil microspheres. Conclusion: Carbopol coated microspheres of ion exchange resin complexes of clarithromycin for the gastro-retentive delivery of clarithromycin can be a promising alternative to the conventional oral solid dosage forms in the control of H. pylori induced chronic gastritis or duodenal ulcers.