Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but increasingly described phenomenon of immune activation and organ dysfunction in association with a wide variety of medications. This reaction shows a broad spectrum of clinical presentation and severity, ranging from mild to lethal. Treatment strategies of immune suppression appear be helpful in some cases, but treatment failures occur frequently with reported mortality rates of 5% to 10%. We present a pediatric case of DRESS syndrome associated with either lamotrigine or bupropion, leading to multiorgan involvement and life-threatening complications of respiratory failure and cardiac arrest. After failing to improve with removal of these medications and administration of systemic corticosteroids, our patient showed dramatic, sustained clinical response to therapeutic plasma exchange. To our knowledge, this is the first reported case of therapeutic plasma exchange used for life-threatening DRESS syndrome in a pediatric patient. This case suggests needed research for this therapeutic option in life-threatening DRESS syndrome resistant to high-dose steroids.