Down syndrome is the leading genetic cause of intellectual disability and automatically qualifies individuals for Social Security Insurance. Therefore, Medicaid is the major health insurance provider for a population at high risk for dementia, obesity, and premature mortality. Despite the importance of Medicaid for adults with Down syndrome, little is known about how this population uses Medicaid. To describe enrollment in, health care use in, and cost to Medicaid for adults with Down syndrome compared with adults with intellectual disability and a random sample of adults enrolled in Medicaid. In this cohort study, the data are from a claims cohort of adults aged 18 years or older enrolled in Medicaid at any point between January 1, 2011, and December 31, 2019. Participants were enrollees with 1 or more inpatient claim or 2 or more other claims with an International Classification of Diseases, Ninth Revision code or an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code for Down syndrome or intellectual disability as well as a random sample of those without developmental disability. Analyses were conducted from June 2022 to February 2023. Data were linked across 2 data reporting systems. Main outcomes were enrollee demographic characteristics, enrollment characteristics, cost, and service use. This cohort study included 123 024 individuals with Down syndrome (820 273 person-years of coverage; mean [SD] age, 35 [14.7] years; median age, 33 years [IQR, 21-48 years]; 51.6% men; 14.1% Black individuals; 16.7% Hispanic individuals; and 74.6% White individuals), 1 182 246 individuals with intellectual disability (mean [SD] age, 37.1 [16.8] years; median age, 33 years [IQR, 22-50 years]; 56.5% men; 22.0% Black individuals; 11.7% Hispanic individuals; and 69.5% White individuals), and 3 176 371 individuals with no developmental disabilities (mean [SD] age, 38 [18.6] years; median age, 33 years [IQR, 21-52 years]; 43.8% men; 23.7% Black individuals; 20.7% Hispanic individuals; and 61.3% White individuals). Median enrollment in Medicaid for a person with Down syndrome was 8.0 years (IQR, 5.0-9.0 years; mean [SD], 6.6 [2.6] years). Costs were higher for the Down syndrome group (median, $26 278 per person-year [IQR, $11 145-$55 928 per person-year]) relative to the group with no developmental disabilities (median, $6173 per person-year [IQR, $868-$58 390 per person-year]). Asian, Black, Hispanic, Native American, and Pacific Islander adults with Down syndrome had fewer costs and claims per person-year compared with White adults with Down syndrome. This cohort study of individuals with Down syndrome enrolled in Medicaid found consistent enrollment and high use of health care in a population with high health care needs. Results were similar comparing individuals with Down syndrome and those with intellectual disability, with both groups differing from a sample of Medicaid enrollees with no developmental disabilities. Medicaid data are a useful tool for understanding the health and well-being of individuals with Down syndrome.