A sensitive HPLC method with fluorescence detection was applied to the analysis of melamine for the first time. The proposed method was successful in enhancing the HPLC sensitivity of melamine through derivatizing the analyte with MASC which was characterized by excellent fluorescence property. Meanwhile, derivatization of hydrophilic melamine with hydrophobic MASC also resulted in the successful retention of the analyte on a widely used C18 reversed phase column with no ion-pair reagents needed. The proposed method was successfully applied to melamine leaching study, and the results indicated that the leaching of melamine from tableware was obvious at high temperature. The labeling strategy also shows powerful potential for the analysis of melamine in other matrices due to the low interferences observed.