Abstract Background Dual antiplatelet therapy causes gastric bleeding and requires incorporation of gastro protective agent. Objectives: Formulation and invitro evaluation of multistage release bilayer tablets containing three active ingredients (clopidogrel, aspirin & ranitidine) for site specific release i.e. stomach & duodenum. Method: Here, immediate release layer of multistage release matrices contains clopidogrel bisulphate granules and enteric coated aspirin pellets. Second layer is gastro retentive floating layer of ranitidine hydrochloride and developed by using HPMC K100 or xanthan gum as release retarding polymer along with Sorb-Cel M® for the very first time as floating agent. Results: Floating lag time, layer separation time, total floating time and swelling of floating layer increased with increasing concentration of polymer and decreasing concentration of Sorb-Cel M®. FTIR and DSC studies indicated absence of drug polymer interaction while XRD indicated amorphous nature of drugs. Cross section electron micrograph of optimized tablets confirmed our idea, showing stable interface between two layers and intact aspirin pellets in immediate layer. During drug release we demonstrated targeted release of three ingredients at their desired site i.e. clopidogrel and ranitidine HCl at pH 1.2 and aspirin at pH 6.8 to avoid its gastric irritating effect. In floating layer xanthan gum provided better controlled release of ranitidine HCl than HPMC K100. Conclusion: So, concisely our developed matrices could potentially delivers three active pharmaceutical ingredients (APIs) at desired site of action combined in single unit. It will not only reduce pill burden on patients but can also overcome the side effects of concomitant administration of aspirin and clopidogrel bisulphate.