This study reports an optimized headspace-solid phase microextraction (HS-SPME) method for the determination of methoxypyrazines in wine. Analysis was performed by using comprehensive two-dimensional gas chromatography with novel detection capabilities, including nitrogen phosphorus detection (GCÃ—GC-NPD) and time-of-flight mass spectrometry (GCÃ—GC-TOFMS). In the latter, stable isotope dilution was performed for the quantitation of 2-methoxy-3-(2-methylpropyl) pyrazine (IBMP), using labelled 2-(2H3)methoxy-3-(2-methylpropyl)pyrazine (d3-IBMP) as the internal standard, and resolution of the two analogues was facilitated using the deconvolution capabilities of the TOFMS. This research represents the first report of HS-SPME with isotope dilution and GCÃ—GC-TOFMS (GCÃ—GC-IDTOFMS). Analysis by GCÃ—GC-NPD enabled detection limits of 0.5 ng/L for the quantitation of IBMP, which was superior to that obtained using GCÃ—GC-IDTOFMS (1.95 ng/L). Nevertheless, both methods were adequately sensitive for real wine analysis, yielding highly comparable IBMP concentrations of 26.1 and 27.8 ng/L, respectively, from a Sauvignon blanc wine. The complexity of the real wine headspace was simplified as a result of selective detection using GCÃ—GC-NPD and, in the case of GCÃ—GC-IDTOFMS, the use of extracted ion chromatograms (EICs).