There is a paucity of information as to whether chromosomal abnormalities, including Down Syndrome, Turner Syndrome, and Klinefelter Syndrome, have an association with atrial fibrillation (AF) and ischemic stroke development. Data from 3660 patients with Down Syndrome, 2408 with Turner Syndrome, and 851 with Klinefelter Syndrome without a history of AF and ischemic stroke were collected from the Korean National Health Insurance Service (2007–2014). These patients were followed-up for new-onset AF and ischemic stroke. Age- and sex-matched control subjects (at a ratio of 1:10) were selected and compared with the patients with chromosomal abnormalities. Down Syndrome patients showed a higher incidence of AF and ischemic stroke than controls. Turner Syndrome and Klinefelter Syndrome patients showed a higher incidence of AF than did the control group, but not of stroke. Multivariate Cox regression analysis revealed that three chromosomal abnormalities were independent risk factors for AF, and Down Syndrome was independently associated with the risk of stroke. In conclusion, Down Syndrome, Turner Syndrome, and Klinefelter Syndrome showed an increased risk of AF. Down Syndrome patients only showed an increased risk of stroke. Therefore, AF surveillance and active stroke prevention would be beneficial in patients with these chromosomal abnormalities.