Fifteen children with infantile spasms and a hypsarrhythmic EEG defined by EEG-videotelemetry monitoring received a regimen of high-dose (150 IU/m2/d) ACTH for their seizures. We carried out an endocrinologic evaluation before and after initiation of the ACTH and conducted a time course study of plasma ACTH and cortisol levels after ACTH dosing. Spasms were controlled and the EEG normalized in 14 of the 15 children. Prior to starting ACTH therapy all the patients had normal prolactin, insulin, cortisol, and ACTH levels in plasma and normal thyroid function. Although the pattern of rise of ACTH levels in plasma after ACTH dosing was similar in all the children, there was great individual variation in the absolute concentrations. However, both the pattern of rise and absolute level of cortisol in plasma after ACTH was highly predictable in all patients. Plasma cortisol rose rapidly within 1 hour of ACTH administration and continued a slower rise for 12 to 24 hours after the ACTH dose. High-dose ACTH therapy seems quite effective in infantile spasms, perhaps because of a sustained high level of plasma cortisol. This sustained plateau of cortisol may be more effective in controlling infantile spasms than the pulse effect expected with oral steroids or lower doses of ACTH.