The adaptive mechanisms that protect some patients with Type I glycogen storage disease from fasting hypoglycemia were examined in two young adults. Both maintained low normal fasting plasma glucose concentrations even during 3 day fasts; blood lactate concentrations increased during the first 12 hr and then decreased to normal during the second and third days. Acute hyperglycemic responses to glucagon nearly doubled after three days of starvation when compared with responses following 12 hr fasts. Enhanced glucagon-induced hyperglycemic changes also were observed following the administration of alcohol or glucocorticoids. However, fructose infusions failed to demonstrate hyperglycemic responses after a 3 day fast, alcohol or glucocorticoids. The present studies demonstrate endogenous glucose production in our patients despite an absence of the enzyme glucose-6-phosphatase. These findings could explain why some patients with Type I glycogen storage disease are protected from fasting hypoglycemia.