A multiclass wide-scope screening of organic contaminants in natural and waste water has been developed and validated for qualitative purposes, i.e. detection and reliable identification of compounds detected in samples at a certain level of concentration. The screening is based on the use of liquid chromatography coupled to quadrupole-time of flight mass spectrometry (LC–QTOF MS) and has been applied to water samples of different origin and matrix composition (surface water, ground water and effluent urban wastewater). Water samples were spiked with a standard mixture of around 150 organic contaminants from different chemical families (including a number of relevant metabolites/transformation products (TPs), at 0.1 and 1 μg/L concentration levels. After solid-phase extraction with Oasis HLB cartridges, sample extracts were analyzed by LC–QTOF MS and the accurate-mass full-spectrum data were processed for qualitative analysis. The presence of at least two ions (typically the (de)protonated molecule and one fragment ion) accurate-mass measured was used for the reliable identification. The screening detection limit (SDL) and the limit of identification (LOI) were established as the main parameters of the screening method. Nearly all compounds could be detected at the lowest concentration tested, but identification was problematic for some compounds at 0.1 μg/L level, especially in wastewater samples. The screening procedure was finally applied to different water samples using a home-made database of around 1100 organic contaminants. It allowed the detection and identification of several antibiotics, anti-inflammatory/analgesics drugs and lipid regulators. Cocaine and its metabolite benzoylecgonine were also frequently detected. In addition, triazine herbicides and their TPs, and fungicides like thiabendazol, carbendazim or imazalil, were also identified in some of the samples.