A method involving headspace solid-phase microextraction (HS-SPME) and comprehensive two-dimensional gas chromatography (GC×GC) coupled to time-of-flight mass spectrometry (TOFMS) was developed and applied to evaluate profiles of volatile compounds present in mainstream tobacco smoke particulate matter trapped on glass fiber filters. Six SPME fibers were tested for the extraction capacities toward selected compounds, showing the best results for the polyacrylate fiber. The optimization of the extraction conditions was carried out using multivariate response surface methodology. Two cigarette types differing in a filter design were analyzed using optimized conditions. A template was built in order to generate comprehensive chemical information, which conceded obtaining consistent information across 24 chromatograms. Principal component analysis (PCA) allowed a clear differentiation of the studied cigarette types. Fisher ratio analysis allowed identification of compounds responsible for the chemical differences between the cigarette samples. Of the selected 143 most important ones, 134 analytes were reduced by the active carbon filter, while for nine, classical cellulose acetate filter was more efficient.