An increasing percentage of patients with new-onset seizures are HIV positive. The evaluation and management is distinctly different from managing the non-HIV-infected patient. Clinicians must be familiar with comorbid infectious etiologies and the relative value of electroencephalogram, imaging, and serum and cerebrospinal fluid laboratory tests. Traditional antiepileptic drug (AED) therapies are contraindicated and may lead to increased HIV viral replication through either directed cellular mechanisms or interference with antiretroviral therapies. Newer AEDs have pharmacokinetic properties that make them reasonable choices, although none have been specifically studied for efficacy or safety in HIV. Lastly, optimal choice of an AED should reflect commonly encountered neurologic and psychiatric comorbidities.