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Langerhans cell histiocytosis (LCH) is a non-malignant disorder, whether localized or disseminated, and usually has a favourable prognosis. A possible relationship between LCH and neoplastic diseases has not been assessed up to now even if a few cases have been recorded. We report two new cases of acute leukemia in children with LCH. The first child had acute lymphoblastic leukemia after untreated LCH; the second developed acute promyelocytic leukemia after LCH treated with vinblastine and etoposide. To our knowledge, this is the first case of secondary leukemia after exposure to an epipodophyllotoxin derivative in a child with benign disease. Cooperative studies of large numbers of LCH patients are needed to evaluate a possible association between LCH and acute leukemia, and to identify common risk factors or predisposing agents if such be present.