Objective: To determine whether acute hyperglycemia adversely affects mental efficiency to the same extent as acute mild hypoglycemia. Study design: We administered a battery of cognitive tests to adolescents studied at hyperglycemic (20 mmol/L [360 mg/dl]), hypoglycemic (3.3 mmol/L [60 mg/dl]), or euglycemic (5.5 mmol/L [100 mg/dl]) targets, which were maintained by an insulin-glucose clamp. The study included 36 children, 9 to 19 years of age (mean = 14.7 years), with diabetes duration more than 2 years (mean = 6.9 years). Results: Cognitive test performance did not deteriorate during hyperglycemia. In contrast, there was a significant decline in performance on all cognitive tests during mild hypoglycemia. Autonomic symptoms did not change significantly during hyperglycemia or during the rapid return from hyperglycemia to euglycemia. Although significant increments in epinephrine and pancreatic polypeptide levels occurred during mild hypoglycemia, no changes in counterregulatory hormones occurred during hyperglycemia. An exploratory regression analysis demonstrated that changes in mental efficiency were best predicted by increases in pancreatic polypeptide, a marker of autonomic activation. Conclusion: These results confirm our previous finding that mild hypoglycemia causes transient decrements in cognitive function. In contrast, neither hyper glycemia, nor the rapid drop from acute hyperglycemia to euglycemia, affected symptoms, cognitive function, or counterregulatory hormone secretion. (J PEDIATR 1995;126:178-84). © 1995 Mosby, Inc. All rights reserved.