Comprehensive two-dimensional gas chromatography coupled to fast acquisition time-of-flight mass spectrometry (GC×GC-TOFMS) is a widely established method for non-targeted analyses. However, for tobacco and tobacco related research, the inherently complex chemical space usually requires the use of a number of different experimental strategies. The development and implementation of a non-targeted GC×GC-TOFMS approach for aqueous samples, e.g. cigarette smoke trapped in phosphate buffered saline (PBS) or microsomal incubation samples is described. The presented approach comprises minimal sample preparation for lowest risk of changing chemical constituent profiles and enables a broad coverage of volatile compounds without the need of using additional methods. Aqueous trapping solution is directly injected on-column and analyzed by GC×GC-TOFMS using a combination of water resistant ionic-liquid based analytical columns. By avoiding any solvent delay, this setup allows the detection of highly volatile furans amongst other constituents. A set of furans was used to test the reproducibility, linearity and robustness of the chromatographic separation. Non-targeted screening of complex matrices such as cigarette smoke trapped in aqueous media is also discussed. This method represents a novel approach, which defies the common belief that aqueous media are incompatible with gas chromatography.