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Abstract: Antiepileptic drug (AED) monotherapy is the preferred initial management approach in epilepsy care, since most patients may be successfully managed with the first or second monotherapy utilized. This article reviews the ration-ale and evidence supporting preferential use of monotherapy when possible and guidelines for initiating and successfully employing AED monotherapy. Suggested approaches to consider when patients fail monotherapy include substituting a new AED monotherapy, initiating chronic maintenance AED polytherapy, or pursuit of non-pharmacologic treatments such as epilepsy surgery or vagus nerve stimulation. Reducing AED polytherapy to monotherapy frequently reduces the burden of adverse effects and may also improve seizure control. AED monotherapy remains the optimal approach for managing most patients with epilepsy