In this study, thermal desorption (TD) two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS) is applied to investigate the chemical composition of the organic fraction of atmospheric particulate matter (PM). The challenges of combining a TD process with GC×GC-TOFMS will be herein addressed with focus directed to the investigation of analytical artifacts. The objective of this study is to demonstrate how the TD process might alter the sample matrix, thus generating uncertain qualitative and quantitative results. Laboratory-generated secondary organic aerosol (SOA) derived from β-pinene oxidation and PM from an urban site (Munich, Germany) were herein investigated. A multistep TD/pyrolysis approach was applied for monitoring thermal decomposition products and oxidations products from TD by varying the maximum desorption/pyrolysis temperature and the temperature gradient ramp. Generally, it has been shown how the thermally labile fraction of the sample matrix will thermally decompose following a trend which is a function of the desorption temperature, the temperature gradient ramp of the heating process, as well as the aerosol chemical composition.