Solid-phase microextraction with comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (SPME-GCxGC-ToFMS) was used for the qualitative analysis of nine non-steroidal anti-inflammatory drugs (NSAIDs) from water. This work focused on the selectivity of the extraction and on the added selectivity provided by the addition of the second column in the chromatography for the analysis of underivatized NSAIDs. Selectivity due to fiber selection, solution pH and extraction temperature is discussed. The final extraction conditions obtained were polydimethylsiloxane/carboxen/divinylbenzene fiber, pH 3.2, temperature 70oC and extraction time 30 minutes. The extracted NSAIDs were then analyzed by GCxGC-ToFMS and the chromatographic selectivity using a combination of a 5% phenyl polydimethyl siloxane column in the first dimension and a trifluoropropyl polysiloxane column in the second dimension is discussed. This method can be applied to determine the NSAIDs in complex matrices such as urine, blood for clinical toxicology for trace level analysis.