Abstract: The method for high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was established for the determination of diclofenac sodium (NSAIDs) in swine muscle, liver or kidney. Naproxen was adapted for internal standard. The samples were pretreated by liquid-liquid extraction, then methanol protein precipitation. Chromatographic separations were performed on an Eclipse Plus C18 column (100 mm×2.1 mm×3.5 μm) with an isocratic elution. Diclofenac and naproxen were ionized with an ESI source operated in negative ion mode, and were measured by selective reactions monitoring mode (SRM). The results show that the relationships of diclofenac sodium in the three tissues are well in the concentration of 0.5-100 μg/kg. The correlation coefficinets are more than 0.99. The RE of accuracy and the CV of precisions are all less than 15%. The method is rapid, specific and reliable, which has been applied to determine the residue of diclofenac sodium in swine muscle, liver or kidney bought from markets.