Abstract: The melamine in aquatic products was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS).We compared the effects of retention and separation of three columns such as C₁₈ column, cyano (CN) column and strong cation exchange and reveraed phase (CR) column. The results showed that with methanol and 5 mmol volatile ion-pair reagent perfluoroheptanoic acid as mobile phase, and with gradient elution, melamine could be separated well in C₁₈ column. This study broadened the applications of C₁₈ column in drug residue analysis. The method, which is cost-effective, sensitive, stable and with good reproducibility, is suitable for determining of melamine residue in aquatic products.