This paper shows the use of ultra-performance liquid chromatography (UPLC) coupled to orthogonal acceleration time of flight mass spectrometry (TOF MS) for the comprehensive screening of 150 veterinary drugs residues in raw milk. Ail easy sample preparation based on protein precipitation associated with ultrafiltration was hyphenated to fast chromatography. This method enabled the screening for more than 50 samples per day and searched for 150 drugs and metabolites including avermectines, benzimidazoles, beta-agonists, beta-lactams, corticoides, macrolides, nitroimidazoles. quinolones. sulfonamides, tetracyclines and some others. Identification of contaminants is based on accurate mass measurement. UPLC-TOF also showed very good performances for quantitation and allowed the determination of majority of compounds below MRL. An in-house validation procedure was conducted based oil European directive 2002/657/EC with measurement of response function, accuracy, repeatability, limits of detection (LOD), decision limit (CC alpha) and detection capability (CC beta). (C) 2009 Elsevier B.V. All rights reserved.