The effect of ketamine, a centrally-acting, nonbarbiturate anesthetic, on plasma corticosterone was studied in male rats. Ketamine administered intraperitoneally (i.p.) at anesthetic and subanesthetic doses (120–15 mg/kg) elicited corticosterone responses of the same magnitude as a pharmacological dose of ACTH. The plasma corticosterone response to ketamine was abolished in 24 h hypophysectomized rats and was blocked by dexamethasone (4 mg/kg i.p., 10 h prior to ketamine). The steroid response to ketamine was not significantly changed by prior systemic treatment with atropine or phentolamine. Pretreatment with propranolol or haloperidol, either singly or in combination, resulted in significant decreases in the corticosterone response to ketamine. These results suggest that the corticosterone response to ketamine is mediated through a facilitatory β-adrenergic and/or dopaminergic pathway or some hybrid thereof, and that ketamine is a convenient and useful agent for testing pituitary adrenal responsiveness in the rat.