SummaryAlthough the treatment of patients with epilepsy who are mentally retarded and have multiple handicaps has generally involved polypharmacy, there is an emerging trend towards simplified antiepileptic drug (AED) regimens. A prospective study of reduction in the number of AEDs was conducted in an institutionalised population of profoundly retarded patients with epilepsy and multiple handicaps. Of 44 patients with uncontrolled generalised seizures who were receiving 4 or 5 AEDs in our study, 28 (64%) achieved monotherapy and the remaining 16 (36%) achieved duotherapy, with significantly improved seizure control and reduced intensity of seizures (although seizure frequency increased transiently in some patients following withdrawal of primidone and phenobarbital). 14 patients (32%) became seizure-free: 13 received monotherapy and I received duotherapy. The remaining patients had ~ 50% reduction in seizure frequency while receiving monotherapy (15 of 28) or duotherapy (15 of 16). The majority of patients who became seizure-free were receiving divalproex sodium or a combination of divalproex and phenytoin. After dosage reduction to regimens with I or 2 drugs, most patients showed more positive behaviours and became more sociable. Overall treatment costs were also markedly reduced. We conclude that AED reduction to mono-or duotherapy is desirable in patients with multiple handicaps and refractory seizures who are receiving polypharmacy regimens.