Four children with adrenal cortical hypofunction were receiving amino-glutethimide in combination with other anticonvulsants. Amino-glutethimide was readministered to one of these patients with development of manifestations and serum electrolyte changes of adrenal insufficiency, with a simultaneous fall in the plasma and urinary 17-hydroxycorticosteroids. Puppies that received amino-glutethimide alone were unresponsive to corticotropin. Histologic alterations of postmortem adrenal specimens in ten of 14 patients receiving amino-glutethimide with other anticonvulsants were reproducible in rats and puppies that received amino-glutethimide alone. Data obtained from studies on humans and animals indicate that defective adrenal steroidogenesis is not due to an adrenocorticotropic hormone (ACTH) deficiency nor to destruction of the adrenal but rather from a blockage in the conversion of cholesterol to Δ5-pregnenolone. This drug may be clinically useful as an adrenal inhibitor.