A new strategy is proposed for the triple drug treatment (tetracycline, metronidazole and bismuth salt) of Helicobacter pylori associated peptic ulcers. The design of the delivery system was based on the swellable asymmetric triple layer tablet approach, with floating feature in order to prolong the gastric retention time of the delivery system. Hydroxypropylmethylcellulose and poly(ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt could be included in one of the outer layers for instant release. The concentration of tetracycline and metronidazole released over time was determined simultaneously on a gradient high-performance liquid chromatography system. Results demonstrated that sustained delivery of tetracycline and metronidazole over 6-8 h can be easily achieved while the tablet remained afloat. The floating aspect was envisaged to extend the gastric retention time of the designed system to maintain effective localized concentration of tetracycline and metronidazole. Additionally, the developed HPLC method for the concurrent determination of tetracycline and metronidazole was proved to be rapid and accurate. The developed delivery system has potential to increase the efficacy of the therapy and improve patient compliance.