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Acute promyelocytic leukemia (APL) is rare in patients with Down syndrome (DS). Cytotoxic chemotherapy combined with all-trans retinoic acid (ATRA) has been a standard treatment for APL, but is potentially intolerable for DS patients because of their vulnerability to cytotoxic agents. We report here a case of a 10-year-old girl with DS and APL successfully treated with a combination of ATRA and arsenic trioxide, a therapy emerging as a new standard for APL. She achieved molecular remission and completed the therapy without significant toxicities. ATRA/arsenic trioxide combination therapy would be a preferable option for DS patients with APL.