Lamotrigine is an anticonvulsant drug soon to be introduced to the North American market. It is chemically unrelated to any currently available antiepileptic drug. The objective of this study was to develop a quantitative high-performance liquid chromatography assay for lamotrigine in serum. Lamotrigine was extracted from serum at alkaline pH into ethyl acetate after addition of the internal standard (BW725C78). After mixing, the organic layer was evaporated to dryness before dissolving the residue in methanol for isocratic separation on a RP-8 column (5 microns) with a mobile phase of water/0.5 M phosphate buffer at pH 6.5/acetonitrile (790/10/200) with eluant monitoring at 306 nm. Calibration was performed with five serum standards (2-32 microM and recovery averaged 88% at 25 microM. Between-run precision was 4.1 and 2.5% C.V. at 13.6 and 31.6 microM, respectively. At room temperature, lamotrigine was stable for a minimum of 7 days. Interference studies were performed on serum specimens containing commonly monitored drugs. The only potentially interfering drug was carbamazepine, which elutes 2.5 times longer than lamotrigine. We conclude that this is a reliable method for quantitation of lamotrigine in serum.