Down syndrome is the most common chromosomal condition, and average life expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite the unique clinical comorbidities among adults with Down syndrome, there are no clinical guidelines for the care of these patients.To develop an evidence-based clinical practice guideline for adults with Down syndrome.The Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome Workgroup (n = 13) developed 10 Population/Intervention/ Comparison/Outcome (PICO) questions for adults with Down syndrome addressing multiple clinical areas including mental health (2 questions), dementia, screening or treatment of diabetes, cardiovascular disease, obesity, osteoporosis, atlantoaxial instability, thyroid disease, and celiac disease. These questions guided the literature search in MEDLINE, EMBASE, PubMed, PsychINFO, Cochrane Library, and the TRIP Database, searched from January 1, 2000, to February 26, 2018, with an updated search through August 6, 2020. Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework, in January 2019, the 13-member Workgroup and 16 additional clinical and scientific experts, nurses, patient representatives, and a methodologist developed clinical recommendations. A statement of good practice was made when there was a high level of certainty that the recommendation would do more good than harm, but there was little direct evidence.From 11 295 literature citations associated with 10 PICO questions, 20 relevant studies were identified. An updated search identified 2 additional studies, for a total of 22 included studies (3 systematic reviews, 19 primary studies), which were reviewed and synthesized. Based on this analysis, 14 recommendations and 4 statements of good practice were developed. Overall, the evidence base was limited. Only 1 strong recommendation was formulated: screening for Alzheimer-type dementia starting at age 40 years. Four recommendations (managing risk factors for cardiovascular disease and stroke prevention, screening for obesity, and evaluation for secondary causes of osteoporosis) agreed with existing guidance for individuals without Down syndrome. Two recommendations for diabetes screening recommend earlier initiation of screening and at shorter intervals given the high prevalence and earlier onset in adults with Down syndrome.These evidence-based clinical guidelines provide recommendations to support primary care of adults with Down syndrome. The lack of high-quality evidence limits the strength of the recommendations and highlights the need for additional research.