The incidence of hematologic disorders in patients with Down's syndrome (DS) is significantly increased, and includes neonatal transient abnormal myelopoiesis and acute leukemias. Treatment of children with DS and leukemia has been controversial because of toxicity and associated congenital cardiac and other abnormalities. The role of BMT, particularly from an unrelated donor (URD), remains undefined in this population. We report two children with DS and acute leukemia successfully treated with intensive chemotherapy and matched URD bone marrow transplantation. One child was transplanted in third remission of ALL and has been disease free for 8 months. A second child with AML was transplanted in second remission and is disease free 15 months post-BMT.