Exercise induced hypoglycemia can occur within hours after exercise in type 1 diabetes mellitus patients. This study tested the hypothesis that an acute exercise bout causes (within hours) blunted autonomic and metabolic responses to subsequent hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Twelve T1DM patients (3W/9M) were studied during a single step, 2hr hyperinsulinemic (572±4 pmol^.l) hypoglycemic (2.8±0.1mmol^.l) clamp two hours after either a hyperinsulinemic euglycemic (AM EUG) or hypoglycemic clamp (AM HYPO), or after sitting in a chair with basal insulin infusion (AM CON) or 90 min of moderate intensity exercise (50% VO_2max, AM EX). Both AM HYPO and AM EX significantly blunted epinephrine responses and muscle sympathetic nerve activity responses to subsequent hypoglycemia compared to both control groups. Endogenous glucose production was significantly lower and the exogenous glucose infusion rate needed to maintain the hypoglycemic level was significantly greater during subsequent hypoglycemia in AM EX vs. CON. Rate of glucose disposal (Rd) was significantly reduced following AM HYPO. In summary, within 2.5h, both moderate intensity EX and HYPO blunted key autonomic counterregulatory responses. Despite this, glucose Rd was reduced during afternoon hypoglycemia following morning hypoglycemia, indicating post hypoglycemic insulin resistance. Following morning exercise endogenous glucose production was blunted, but glucose Rd was maintained during afternoon hypoglycemia, thereby indicating reduced metabolic defenses against hypoglycemia. These data suggest that exercise-induced counterregulatory failure can occur very rapidly increasing the risk for hypoglycemia in T1DM within hours.