The efficacy of lamotrigine (LTG), a new antiepileptic drug (AED) chemically unrelated to drugs in current use, was evaluated in 21 in-patients (18 males, 3 females; mean age 34.6; range 23-42 years) with severe refractory epilepsy. An add-on double-blind placebo-controlled crossover design was used, with 12 week treatment periods, and a 6 week washout period. Subjects were allocated to 1 of 2 dosing schedules according to their concomitant AEDs. Doses were increased according to clinical response. Although there was no significant reduction in total seizure count during the lamotrigine treatment period compared to placebo, there appears to be a drug effect as there was a marked reduction in generalized tonic-clonic seizures in favour of lamotrigine in the last 4 weeks of the treatment period. There was no significant difference in volunteered adverse experiences during active and placebo treatment. Concomitant serum AED concentrations, biochemical and haematological parameters were unaffected by lamotrigine treatment.