Screening of a large number of emerging pollutants is highly desirable for the control of water quality. In this respect, a novel, fully automated contaminant screening method based on an integrated sample preconcentration and liquid chromatography coupled to high resolution mass spectrometry (SPE-UHPLC-HRMS) has been developed. The optimal chromatographic column and experimental conditions allowing the retention and subsequent elution of the maximum number of analytes were defined. Liquid chromatography and Q-exactive (Orbitrap (TM)) parameters were optimized to obtain the best separation of molecules of interest, and the lowest detection limits. Due to the large amount of data to compare, a script written in R language was developed to evaluate the quality of the data generated by the comparison of 14 experimental conditions. The developed method enables the simultaneous semi quantitative analysis of 539 compounds (pesticides and drug residues), in 36 min with only 5 mL of water. Method validation was achieved through studies of repeatability, selectivity, linearity and matrix effect. Application to 20 tap water samples collected in and around Paris showed the presence of 34 different compounds all with concentrations below 0.1 mu g/L, the European Union limit for drinking water. Pesticides and transformation products frequently found in water resources such as atrazine and its metabolites, hexazinone, oxadixyl, propazine and simazine were detected. Drug residues such as valsartan and carbamazepine, usually not monitored, were also found. The next step will be to assess the ability of this method to highlight the presence of unexpected contaminants not present in our database. (C) 2016 Elsevier Ltd. All rights reserved.