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A simple, sensitive and validated HPLC method has been developed to determine esomeprazole and domperidone in tablet dosage form. The chromatographic separation was achieved on a hyperchrome C-18 column column (4.6 x 150mm, 5µ particle size) analytical column using a mixture of acetonitrile: Phosphate buffer (pH 5.0) in the ratio of 60:40 (v/v) used as the mobile phase, at a flow rate of 1.0 ml/min and detector wavelength at 290 nm. The validation of the proposed method was carried out for specificity, linearity, accuracy, precision, limit of detection, limit of quantitation and robustness. Linearity of method was found to be in concentration range 10-50 µg/ml for esomeprazole and 5-25 µg/ml for domperidone with correlation coefficient greater than 0.9999. The retention time of domperidone and esomeprazole was found to be 2.92 and 3.91 min respectively. The method can be used for simultaneous determination of esomeprazole and domperidone.