Abstract Disclosure: W. Huang: Consulting Fee; Self; Spruce Biosciences. Research Investigator; Self; Spruce Biosciences. R. Charlton: Employee; Self; Spruce Biosciences. S. Sile: Employee; Self; Spruce Biosciences. C. Dieyi: Employee; Self; STATinMED. S. Adams: Employee; Self; STATinMED. J. Maynard: Employee; Self; STATinMED. C.N. Barnes: Employee; Self; Spruce Biosciences. A.H. Hamrahian: Consulting Fee; Self; Spruce Biosciences. Research Investigator; Self; Spruce Biosciences. Background and Aims: Classic congenital adrenal hyperplasia (CAH) is a group of autosomal recessive conditions that affects the production of adrenal hormones, leading to deficiencies in cortisol and aldosterone, and excess in adrenal androgens. Current treatment includes mineralocorticoids and oral glucocorticoids (GCs) for physiologic cortisol replacement and hypothalamic-pituitary-adrenal (HPA) axis suppression to control androgen levels. The health impacts of hyperandrogenemia include accelerated skeletal maturation leading to adult short stature, precocious puberty, acne, hirsutism, male pattern baldness, adrenal rest tumors, and infertility. There are also serious adverse events due to the long-term use of supraphysiologic doses of GCs. The aim of this study was to explore the risks associated with CAH diagnosis and treatment. Methods: This cross-sectional study used medical administrative claims data within 2014-2021 from RWD Insights®, an all-payer claims database in the US. Adult patients were required to have a diagnosis of CAH (ICD-9/10-CM: 255.9, E25.0, E25.9) and continuous use of oral GCs (defined as a proportion of days covered of 75% or more in any given calendar year). Patients were further required to receive an average daily GC dose of ≥10mg/day hydrocortisone equivalent and be free of pituitary disorders. Non-CAH controls were also selected if they did not have a CAH diagnosis or any GC use. Demographic characteristics and comorbidity rates were compared between patients with and without CAH during the study period. For comorbidity rate comparisons, rate ratios (RR) and 95% confidence intervals (CI) were computed. Results: A total of 1,532,141 (CAH: 2,033; Non-CAH: 1,530,108) were eligible for the study. A lower proportion of the CAH cohort was elderly (i.e., 65+ years; 11% vs. 26%), and there were more females (67% vs. 57%), as compared to the non-CAH cohort. After propensity score matching (PSM) on demographic characteristics, there were 2,019 and 8,076 patients in the CAH and non-CAH cohort, respectively, and patient characteristics were balanced. There were higher rates of comorbidities in the CAH cohort. Some notable differences, RR (95%CI), include GC related comorbidities such as osteoporosis/necrosis, 3.48 (3.36, 3.60) and fractures, 2.14 (1.90, 2.39); metabolic disorders, 2.20 (2.08, 2.33), obesity, 1.35 (1.26-1.44), type 2 diabetes, 1.27 (1.18,1.36), and cardiovascular disorders, 1.24 (1.16, 1.33); and CAH related comorbidities, hirsutism, 11.70 (11.34, 12.06) and testicular hypofunction, 5.48 (5.24, 5.71). Conclusions: This study suggests the association of several comorbidities with CAH, highlighting the burden of both the disease and treatment. Novel, non-steroidal treatments that improve hormonal balance in CAH could ameliorate the systemic risks associated with hyperandrogenemia and chronic overexposure to GCs. Presentation: 6/1/2024