To describe the clinical profiles of five patients with Down syndrome and elevated levels of antiphospholipid antibodies. Medical records of all 149 patients screened for anticardiolipin antibodies (aCL) in the pediatric hematology or pediatric rheumatology clinics at New England Medical Center between 1996 and 1998 were retrospectively reviewed, and patients with Down syndrome identified. Thirty-four patients (23%) had elevated IgG titers of aCL antibodies. Of these, five had Down syndrome (15%). Two presented with discoloration of the distal digits, and one each with thrombocytopenia, autoimmune hepatitis, and undifferentiated autoimmune disease. The mothers of two of the four individuals with available family history had experienced frequent miscarriages. An association may exist between Down syndrome and antiphospholipid antibodies, in particular an increased frequency of aCL antibodies. Screening patients with Down syndrome and certain clinical findings may prove useful.