Migration of melamine into foods from melamine tableware has been object of recent Rapid Alert System for Food and Feed (RASFF) notifications. In this context, a rapid and sensitive desorption electrospray ionization-high resolution mass spectrometry (DESI-HRMS) method was developed and validated for the determination of melamine migration from plastic materials. The migration test was performed using acetic acid 3% (w/v) as food simulant. Evaluation of DESI parameters in terms of choice of support, motion profile, geometrical configuration and operating conditions coupled to the use of an orbitrap mass analyzer allowed to achieve significant improvements in terms of selectivity and accuracy obtaining detection and quantitation limits at low microgram per kilogram level. A LC–ESI-MS method was also developed for confirmatory purposes. Both methods were applied to 44 melamine tableware samples available on Italian market in order to assess their compliance with the law. Different concentration levels ranging from 0.0077370.0006 to 3.070.1 mg/kg were found after the third exposure to the simulant in new and used tableware with two samples out of 44 being characterized by a melamine release higher than the legal limit, i.e. 2.5 mg/kg. A two tailed t-test allowed to assess the good agreement between the quantitative results obtained applying the DESI-MS method with those provided by LC–ESI-MS, thus proving reliability of DESIHRMS as rapid technique for the study of melamine release from plastic materials.