The potential of gas chromatography coupled to high-resolution time-of-flight mass spectrometry (GC/TOF-MS) for screening of organic pollutants in water has been explored. After optimization of the solid-phase microextraction (SPME) step, where parameters such as fiber selection and addition of salt were studied, this extraction technique was applied to the analysis of different types of water samples. Investigation of 60 target organic pollutants, including pesticides, octyl/nonyl phenols, pentachlorobenzene, and polycyclic aromatic hydrocarbons (PAHs) was carried out by evaluating the presence of up to five representative m/z ions per analyte, measured at high mass accuracy, and the attainment of their Q/q (Q, quantitative ion; q, confirmative ion) intensity ratio. This strategy led to the detection of 4-t-octylphenol, simazine, terbuthylazine, chlorpyrifos, terbumeton, and terbutryn in several water samples at low part-per-billion levels. Full spectrum acquisition data generated by the TOF-MS analyzer also allowed subsequent investigation of the presence of polybrominated diphenyl ethers and several fungicides in samples after MS data acquisition, without the need to reanalyze the water samples. In addition, nontarget analysis was also tested by application of a deconvolution software. Several organic pollutants that did not form a part of the list of contaminants investigated were identified in the water samples, thanks to the excellent sensitivity of TOF-MS in full spectrum acquisition mode and the valuable accurate mass information provided by instrument. Bisphenol A, the antioxidant 3,5-di-tert-butyl-4-hydroxy-toluene (BHT), its metabolite 3,5-di-tert-butyl-4-hydroxybenzaldehyde (BHT-CHO), the polycyclic musk galaxolide, and the UV filter benzophenone were some of the compounds present in the water samples analyzed. SPME in combination with GC/TOF-MS has been proved to be an attractive and powerful approach for the rapid screening of multiclass organic pollutants in water, with very little sample manipulation and no solvent consumption. This combination provides to the analyst with information-rich MS data that facilitates the reliable identification of many different organic compounds in samples.