Megace (M) is a synthetic progestational agent used to promote weight gain in HIV-infected children. Its effect on adrenal function in children is not known, but associated adrenal suppression has been reported in 4 adults. Standard ACTH stimulation tests (measurement of Cortisol (F) at baseline and one hour after 0.25 mg ACTH) were performed on 18 HIV-infected children, 9 treated with M and 9 age-matched controls. 8 case-control pairs were CDC class C and one pair met CDC class B criteria for HIV disease. There were no significant differences in viral load, antiretroviral, or Ol prophylaxis/therapy between cases and controls; no patients were taking agents known to suppress adrenal function (e.g. ketoconazole, rifampin). One hour F responses >15 mcg/dl were considered normal. Baseline F level and responses to ACTH stimulation were grossly subnormal in 6/9 M- treated patients (<1 mcg/dl at baseline; median one hour F response 2.5±4.5); all controls had normal baseline and ACTH response levels of F (p<0.003). The adrenal suppressive effect of M was evident after as few as 7 weeks of therapy and did not appear to be dose-dependent. Adrenal function normalized in two patients following discontinuation of M that overlapped with a tapering course of glucocorticoid replacement. CONCLUSION: M's asymptomatic adrenal suppressive effect in HIV-infected children may have serious consequences. ACTH stimulation testing should be performed on all HIV-infected children treated with M. Discontinuation of M in adrenally-suppressed children should be gradual and overlapped with F replacement, and HIV-infected children taking M may require stress dose steroids during acute illnesses.