The insulin and glucose responses to glucagon infusions (27 microgram/hr) were determined in sheep before and after parenteral lead treatment (6 mg/kg intravenously). Glucose production was measured by primed continuous infusion of [6-3H]glucose. Glucagon and insulin concentrations before and during glucagon infusions were not significantly different between lead treatment and control experiments. Lead administration did not affect the concentration or production of glucose in the preinfusion period. However, depressed hyperglycemia during glucagon infusion in lead treated experiments tended to be associated with decreased glucose production. The reduced glucogenic response to glucagon may be the result of reduced function of pyruvate carboxylase, a key hepatic gluconeogenic enzyme in sheep, from lead induced impairment of mitochondrial function.