Background. Individuals with rare disorders, like Down syndrome (DS) are historically understudied. Currently, it is not known how COVID-19 pandemic affects individuals with DS. Herein, we report an analysis of individuals with DS who were hospitalized with COVID-19 in the Mount Sinai Health System in New York City, USA. Methods. In this retrospective, single-center study of 4,615 patients hospitalized with COVID-19, we analyzed all patients with DS admitted in the Mount Sinai Health System. Hospitalization rates, clinical and outcomes were assessed. Findings. Contrary to an expected number of one, we identified six patients with DS. We found that patients with DS are at an 8.9-fold higher risk of hospitalization with COVID-19 when compared to non-DS patients. Hospitalized DS individuals are on average 10 years younger than non-DS patients with COVID-19. Moreover, type 2 diabetes mellitus appears to be an important driver of this susceptibility to COVID-19. Finally, patients with DS have more severe outcomes than controls, and are more likely to progress to sepsis in particular. Interpretation. We demonstrate that individuals with DS represent a higher risk population for COVID-19 compared to the general population and conclude that particular care should be taken for both the prevention and treatment of COVID-19 in these patients.