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Recent concerns have been raised by neurologists and patients with epilepsy regarding the bioequivalence of generic lamotrigine to the brand Lamictal. Bioequivalence studies require the quantification of lamotrigine in human plasma, including in the presence of other drugs, for studies that will use patients with epilepsy rather than healthy volunteers.Lamotrigine was extracted from plasma through a simple protein precipitation and analyzed by fast liquid chromatography coupled to heated electrospray ionization with tandem mass spectrometric detection. A backflush step to remove interferent accumulation on column was included, and a stable isotope-labeled lamotrigine was used as an internal standard. The method was validated for accuracy, precision, interday and intraday coefficient of variation, specificity, lower limit of detection, lower limit of quantification, linearity, range, instrument precision, freeze–thaw, dilution integrity, and sample stability. Specificity evaluation included consideration of the impact of other antiepileptic drugs.The described method has a linear range of 8–10,000 ng/mL of lamotrigine (r2 = 0.9999) and a lower limit of detection of 1 ng/mL and a lower limit of quantification of 8 ng/mL. Intraday and interday reproducibility were less than 10.0% relative SD and 10.4% relative SD, respectively, and the percent recovery varied from 96.6% to 109.3% at various lamotrigine concentrations. A backflush step reduced matrix effects and no interference peak from plasma or other antiepileptic drugs were observed.A liquid chromatography–heated electrospray ionization–tandem mass spectrometry method including a backflush step was developed and validated to measure lamotrigine concentration in patient plasma. The method will be applied to bioequivalence studies that compare brand versus generic lamotrigine.