Epilepsy is a clinical phenomenon in which a person has recurrent seizures due to a chronic underlying process. Approximately 1 to 3 percent of people in the United States will develop epilepsy over the course of their lives. Epilepsy begins most commonly during the first 9 years of life, plateaus over the next 30 years, dips in patients 40 to 59 years of age, and then rises again in the elderly. Seizures in epilepsy can result in status epilepticus, a life-threatening unrelenting seizure, or can result in car accidents or falls that can lead to morbidity or mortality. In addition, uncontrolled seizures can result in patients losing their jobs or driving privileges. The main three types of seizures in patients with epilepsy include partial, generalized, and unclassified. There are several distinct subtypes of seizures. Since 1993, the Food and Drug Administration (FDA) has approved several newer antiepileptic drugs (felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, zonisamide) for the treatment of epilepsy. This offered clinicians and patients many new options over the older antiepileptic medications that were approved between 1953 and 1983 (phenytoin, 1953; primidone, 1954; ethosuximide, 1960; carbamazepine, 1968; clonazepam, 1975; divalproex, 1978; valproic acid, 1983). The comparative benefits and harms of older versus newer antiepileptic drugs have been assessed in numerous randomized controlled trials with varying results. Another important issue in the management of epilepsy is generic substitution of innovator antiepileptic medications. The American Academy of Neurology has issued two position papers stating that there is concern with generic antiepileptic medication substitution and that physicians should specifically approve all generic substitutions. . The Italian League Against Epilepsy established a working group on generic products in epilepsy treatment. It concluded that generic medications offer a valuable and cost-effective choice in the management of epilepsy but that generic substitution is not recommended in patients who achieve seizure remission on an innovator product. The FDA and the American Society of Health-System Pharmacists do not share the view that antiepileptic medications, or other narrow therapeutic index medications (medications where the difference between the minimum effective and minimum toxic concentrations are close together), should be treated differently as it pertains to generic substitution. This CER utilized data on benefits and harms from direct comparative studies of newer versus older or innovator versus generic antiepileptic medications in patients with epilepsy. Key Question 1: In patients with epilepsy, what is the comparative effectiveness/efficacy of antiepileptic medications on health outcomes: mortality, hospitalizations, office/emergency department visits, composite endpoint of medical service utilization, health-related quality of life, seizures, secondary seizure injury, status epilepticus, loss of driver's license, and loss of employment? Key Question 2: In patients with epilepsy, what is the comparative effectiveness/efficacy of antiepileptic medications on intermediate outcomes: pharmacokinetics, the comparative dose of medication needed to control seizures, and switchback rates? Key Question 3: In patients with epilepsy, what is the comparative impact of antiepileptic medications on serious adverse events such as neurological adverse effects, hypotension, rash, suicidal ideation, mood and cognition, bone density, and cosmetic adverse effects? Key Question 4: In patients with epilepsy, what are the comparative benefits or harms for antiepileptic medications in subgroups of patients differentiated by seizure etiology, seizure type, gender, ethnicity, patient age, and patient pharmacogenetic profile; and by types of antiepileptic medication?