Congenital adrenal hyperplasia (CAH) is associated with poor health outcomes. This is, in part, because doses of glucocorticoid sufficient to suppress excess adrenal androgens are also associated with adverse metabolic effects such as insulin resistance. This toxicity occurs with efficacious doses of all commonly prescribed glucocorticoids (hydrocortisone, prednisolone and dexamethasone). However, the glucocorticoid corticosterone may have an improved therapeutic index because of its unusual susceptibility to export from cells by ATP-binding cassette (ABC) transporters. ABCB1 is expressed in the brain and exports cortisol (hydrocortisone), prednisolone and dexamethasone, limiting their potency at suppressing ACTH. However, corticosterone is not exported by ABCB1 but is exported by ABCC1. Expression of ABCC1 is relatively low compared to ABCB1 in brain, however it is expressed in the absence of ABCB1 in adipose tissue, muscle and bone, potentially limiting corticosterone action in these tissues. We hypothesised that corticosterone may be more efficacious at suppressing ACTH and adrenal androgens but with less metabolic toxicity than hydrocortisone. Fourteen adults with classic CAH due to 21-hydroxylase deficiency were recruited to a double-blind randomised crossover study comparing intravenous infusions of placebo, hydrocortisone and deuterated (D8) corticosterone. Subjects attended after omitting their usual glucocorticoid for 12h and were administered glucocorticoid/placebo for 5.5 hours in a two-step infusion designed to achieve concentrations of 400 and 800 nM. Blood samples were collected regularly. Circulating D8-corticosterone concentrations were approximately 30% higher than hydrocortisone. D8-corticosterone suppressed ACTH, androstenedione and 17-hydroxyprogesterone to a greater extent than hydrocortisone. However, hydrocortisone increased circulating insulin compared with D8-corticosterone and placebo (10.0±1.3 vs 8.3±1.2 vs 7.2±1.3 mU/l respectively, P<0.05). Blood pressure and FFAs were similar between phases. Thus, corticosterone acutely suppresses ACTH and adrenal androgens in CAH patients without causing hyperinsulinaemia. Corticosterone may be a better glucocorticoid replacement than hydrocortisone for the treatment of CAH.