A specific, accurate, precise and reproducible stabilityindicating HPLC method has been developed and subsequently validated for the simultaneous determination of pantoprazole, rabeprazole, lansoprazole and domperidone in commercial tablets. The proposed HPLC method utilizes Phenomenex Gemini C18 column (150 mm 4.6 mm i.d., 5 μm) and mobile phase consisting of methanol-acetonitrile-20 mM dipotassium hydrogen phosphate and phosphoric acid buffer pH 7.0 (20:33.11:46.89, v/v/v) at a flow rate of 1.10 mL/min. Quantitation was achieved with UV detection at 280 nm based on peak area with linear calibration curves at concentration ranges 1.0-10μg/ml for pantoprazole & rabeprazole, 0.75- 7.5μg/mL for lansoprazole and 0.5-5.0μg/mL for domperidone (R2 > 0.999 for all drugs). The method was validated in terms of accuracy, precision, linearity, limits of detection, limits of quantitation and robustness. This method has been successively applied to pharmaceutical formulation and no interference from the tablet excipients was found. Pantoprazole, rabeprazole, lansoprazole, domperidone and their combination drug product were exposed to acid, base and neutral hydrolysis, oxidation, dry heat and photolytic stress conditions and the stressed samples were analyzed by the proposed method. As the proposed method could effectively separate the drug from its degradation products, it can be employed as stability-indicating method for the determination of instability of these drugs in bulk and commercial pharmaceutical formulations.