Persons with Down syndrome (DS) are presumed to be at high risk of severe CoVID-19, due to immune dysregulation and often compromised cardiopulmonary function. Aim of the present study is to assess epidemiological and clinical characteristics of individuals with DS deceased in Italian hospitals with CoVID-19. We used a nationwide database of 3,438 patients deceased with RT-PCR-confirmed SARS-CoV-2 infection in Italy (10.4% of all deaths with CoVID-19 in the country at the time of analysis). Data on demographics, pre-existing comorbidities and in-hospital complications leading to death were extracted from medical charts obtained from hospitals. Data on individuals with DS deceased with CoVID-19 were obtained from this sample. Sixteen cases of death in individuals with DS (0.5% of all charts analyzed) were identified. Acute respiratory distress syndrome occurred in all 16 cases. Compared with individuals without DS, those with DS deceased with CoVID-19 were younger (52.3 ± 7.3 vs. 78.1 ± 10.6 years, p < .001) and presented a higher incidence of superinfections (31.2 vs. 13.0%, p = .029). Autoimmune diseases (43.8 vs. 4%, p < .001), obesity (37.5 vs. 11%, p = .009), and dementia (37.5 vs. 16.3%, p = .012) were more prevalent in individuals with DS. ICU admissions was similar in both groups (25 vs. 18.8%, p = .129). Individuals with DS deceased with CoVID-19 are younger than individuals without DS. Comorbidity burden and increased risk of complications (i.e., bacterial superinfections) can influence CoVID-19 prognosis in individuals with DS. Specific strategies to prevent and mitigate the effects of CoVID-19 in the population with DS are needed.