||New chemometric approaches were applied to high performance liquid chromatography (HPLC) for simultaneous determination of esomeprazole magenisum trihydrate and naproxen in their synthetic mixture. These chemometric approaches were applied to the multiwavelength HPLC peak area ratio obtained by plotting the chromatograms at the five wavelengths using diclofenac sodium as internal standard (IS). The multichromatograms were obtained by using the diode array detector (DAD). A mixture of 20 mM acetate buffer (pH=4.2) and acetonitrile (35:65, v/v) was used as a mobile phase on a 5µm (4.6 x 250mm) Inertsil® C18 Column at a flow rate of 1.5 mL/min to separate and determine the investigated drugs in their synthetic mixture. For comparison purposes, a new validated developed classic HPLC method at 299 nm was used to confirm the results obtained from HPLC-chemometric calibration techniques. There was no significant difference between the methods compared.