This scoping review and retrospective medical record review is focused on potential sex differences in cardiovascular diseases in patients with Down syndrome. We limited our review to peer-reviewed, primary articles in the English language, in the PubMed and Web of Science databases from 1965-2021. Four categorical domains were identified and searched using additional keywords: 1) congenital heart disease, 2) baseline physiology and risk factors, 3) heart disease and hypertension, and 4) stroke and cerebrovascular disease. Articles were included if they reported male and female distinct data, participants with Down syndrome, and one of our keywords. The retrospective medical record review was completed using 75 participating health care organizations to identify the incidence of congenital and cardiovascular diseases and to quantify cardiovascular risk factors, in male and female patients. Female patients with Down syndrome are at higher risk of hypertension, ischemic heart disease, and cerebrovascular disease. The risk of congenital heart disease is higher in males with Down Syndrome, at all ages included in our analyses. Some of the male:female sex differences in cardiovascular disease risk in the general patient population are not present, or reversed in the Down syndrome population. This information should be considered for future investigations and ongoing patient care.