Severe hypoglycemia occurs in intensively treated patients with Type 1 Diabetes (T1DM) due in part to deficient epinephrine counterregulatory responses. Previously, we have found that T1DM patients demonstrated a spectrum of altered responses to epinephrine at a variety of target organs as compared to nondiabetic healthy subjects. What is not known is whether intensive glycemic control further modifies target organ responses in individuals with Type 1 Diabetes. Therefore, the aim of this study is to assess whether there is tissue specific (liver, muscle, adipose tissue, pancreas and cardiovascular) resistance to epinephrine in intensively controlled (IC) T1DM as compared to those with conventional control (CC). 8 IC patients (age 33±4yr,BMI 24±2 kg/m², HbA₁C 6.7±0.1%), and 11 CC patients (age 35±3yr, BMI 25±1 kg/m², HbA₁C 9.6±0.1%) underwent two separate randomized, single-blind 2 hour hyperinsulinemic-euglycemic clamp studies with (EPI) and without (NO EPI) epinephrine infusion. Epinephrine levels during EPI were similar in all groups (5197±344 pmol/l). Glucose (5.3 mmol/l±0.1) and insulin levels (515±44 pmol/l) were similar in all groups during the glucose clamps. Endogenous glucose production (EGP) and glucose uptake (Rd) were determined using 3-H³-glucose. Muscle biopsy was performed at the end of each study. IC had a significantly reduced EGP and Rd responses to EPI as compared to CC. Glucagon (GGN) responses to EPI were similarly blunted in both IC and CC. Free fatty acids (NEFA) and glycerol response to EPI was greater in CC as compared to IC. There was a significantly greater systolic blood pressure response to EPI in CC. We conclude that despite similar epinephrine, insulin, and glucose levels, intensively treated T1DM patients had reduced cardiovascular, skeletal muscle, hepatic and adipose target organ responses to EPI as compared to conventionally treated T1DM patients.