Lamotrigine (lamictal) is a new anticonvulsant drug recently approved by the FDA for clinical use. Therapeutic monitoring of lamotrigine is useful for patient management (therapeutic range 1-4 microg/ml). Here we describe a gas chromatography-mass spectrometric identification and quantitation of lamotrigine after extraction from human serum and derivatization. Lamotrigine was extracted from alkaline serum with chloroform and derivatized with N-methyl-N-(tert.-butyldimethysilyl) trifluoroacetamide containing 2% tert.-butyldimethylchlorosilane. Oxazepam-d5 was used as an internal standard. The tert.-butyldimethylsilyl derivative of lamotrigine showed distinct molecular ions at m/z 483 and 485 as well as other peaks at m/z 426, 370 and 334 for unambiguous identification. The base peak was observed at m/z 199. Similarly, the tert.-butyldimethysilyl derivative of oxazepam-d5 showed molecular ions at m/z 519 and 521 along with other characteristic peaks at m/z 462, 376 and 318. For the analysis of lamotrigine, the mass spectrometer was operated in the selective ion monitoring mode. The within-run and between-run precisions were 4.3% (mean=3.01, S.D.=0.13 microg/ml) and 5.1% (mean=2.93, S.D.=0.15 microg/ml), respectively at a serum lamotrigine concentration of 3.0 microg/ml. The within-run and between-run precisions were 8.2% (mean=0.49, S.D.=0.04 microg/ml) and 10.6% (mean=0.47, S.D.=0.05 microg/ml), respectively at a serum lamotrigine concentration of 0.5 microg/ml. The assay was linear for serum lamotrigine concentrations of 0.5-20 microg/ml. The detection limit was 0.25 microg/ml. The assay was free from interferences from common tricyclic antidepressants, benzodiazepines, other common anticonvulsants, salicylate and acetaminophen.