Letterer–Siwe disease, (LSD) or Abt-Letterer-Siwe disease, is one of the four recognized clinical syndromes of Langerhans cell histiocytosis (LCH) and is the most severe form, involving multiple organ systems such as the skin, bone marrow, spleen, liver, and lung. Oral cavity and gastrointestinal involvement may also be seen. LCH and all its subtypes are characterized by monoclonal migration and proliferation of specific dendritic cells.

The subcategorization of Letterer-Siwe disease is a historical eponym. Designating the four subtypes of LCH as separate entities are mostly of historical significance, because they are varied manifestations of the same underlying disease process, and patients also often exhibit symptoms from more than one of the four syndromes.

Letterer-Siwe causes approximately 10% of LCH disease. Prevalence is estimated at 1:500,000 and the disease almost exclusively occurs in children less than three years old. It is more common among Caucasian patients than in African American patients. Children with LCH with single organ involvement tend to have a better prognosis than patients with the multi-system involvement seen in Letter-Siwe disease. The name is derived from the names of Erich Letterer and Sture Siwe.