Twenty-eight children with Down syndrome (DS) and acute lymphocytic leukemia (ALL) were compared to non-DS control leukemics matched by age, white blood cell (WBC) count, and treatment protocol to evaluate presenting manifestations, toxicity, and outcome. The DS children with ALL did not have unique clinical or biologic characteristics to distinguish their disease from that of non-DS patients. Eleven of the DS patients had successfully banded cytogenetic studies of their leukemic cells with the distribution of model chromosome number of 46 (n = 1), 47 (2), 48 (5), and greater than 50 (3). The abnormal leukemic line involved an isochromosome of the long arm of chromosome 9[i(9q)] in 3 cases. Multiagent chemotherapies induced complete remissions in 25 patients (85%), yet overall 5 year event-free survival was only 23 +/- 8% when compared to 64 +/- 9% for control children receiving similar therapies (P less than 0.01). A significant cause of treatment failure was late marrow recurrence in the DS children. Host toxicity was striking in these children. Severe congenital heart disease present in one-third contributed to 2 deaths during antileukemia therapy. Hyperglycemia secondary to diabetogenic agents and repeated bronchitis were common toxicities. Intolerance to the antifolate methotrexate with severe gastrointestinal and skin toxicities was universal. We conclude that the poor prognosis for the child with DS and ALL stems in part from their increased risk of complications and toxicity from intensive modern leukemia therapies, specifically antifolates.