We studied the effects of two structurally unrelated inhibitors of the fatty acid cyclooxygenase and of alpha and beta adrenergic blockade on the elevated plasma levels of 13,14-dihydro-15-keto-prostaglandin (PG)E 2, 6-keto-PGF 1α and thromboxane(TX)B 2, the stable derivatives of PGE 2, PGI 2 (prostacyclin) and TXA 2, respectively, in rats with streptozotocin-induced diabetic ketoacidosis (DKA). Meclofenamic acid and indomethacin each produced a significant decrease in the elevated plasma levels of 13,14-dihydro-15-keto-PGE 2, 6-keto-PGF 1α and TXB 2. Phentolamine significantly reduced the plasma level of TXB 2 but had no effect on the elevated circulating levels of glucose, free fatty acids, total ketones, 13,14,-dihydro-15-keto-PGE 2 or 6-keto-PGF 1α. Propranolol significantly reduced the elevated circulating levels of glucose, free fatty acids and total ketones but had no effect on the levels of the three prostaglandin derivatives. The ability of meclofenamic acid and indomethacin to reduce the plasma levels of 13,14-dihydro-15-keto-PGE 2, 6-keto-PGF 1α and TXB 2 confirms that the plasma levels of these three derivatives are elevated in rats with DKA. Since abnormalities in the production of PGI 2 and perhaps other cyclooxygenase derivatives may contribute to the pathogenesis of certain important hemodynamic and gastrointestinal features of DKA, cyclooxygenase inhibitors may play a role in the management of selected patients with this disorder. Alpha adrenergic activity is essential for the maintenance of the elevated plasma TXB 2 level in rats with DKA. The fall in the plasma TXB 2 level during alpha adrenergic blockade appears to reflect inhibition of platelet aggregation and platelet TXA 2 production, but other sources of the elevated plasma TXB 2 level in DKA are not excluded. Beta adrenergic activity contributes to the maintenance of elevated circulating levels of glucose, free fatty acids and total ketones in experimental DKA but not to the elevated plasma levels of the prostaglandin derivatives.