The incidence of acute myelogenous leukemia (AML) in patients with constitutional trisomy 21 is estimated to be 1 in 300; it is usually seen before age four. Clinical and epidemiological data confirm the improved life expectancy of patients with Down syndrome and their increased susceptibility to the development of leukemia, among other cancers. The most frequent subtype of AML associated with Down syndrome is acute megakaryoblastic leukemia (FAB: M7). The description of acute promyelocytic leukemia (APL) in adult patients with Down syndrome is exceedingly rare. Herein, we describe the unusual presentation, treatment, results, and clinical course of an adult patient with APL and constitutional trisomy 21 and provide a brief review of the literature.