The role of epinephrine and norepinephrine in contributing to the alterations in hepatic glucose metabolism during a 70-h stress hormone infusion (SHI) was investigated in four groups of chronically catheterized (20-h-fasted) conscious dogs. SHI increased glucagon (~5-fold), epinephrine (~10-fold), norepinephrine (~10-fold), and cortisol (~6-fold) levels. Dogs received either all the hormones (SHI; n = 5), all the hormones except epinephrine (SHIEpi; n = 6), or all the hormones except norepinephrine (SHINE; n = 6). In addition, six dogs received saline only (Sal). Glucose production (R_a) and gluconeogenesis were assessed after a 70-h hormone or saline infusion with the use of tracer ([3-³H]glucose and [U-¹⁴C]alanine) and arteriovenous difference techniques. SHI increased glucose levels (108 ± 2 vs. 189 ± 10 mg/dl) and R_a (2.6 ± 0.2 vs. 4.1 ± 0.3 mg · kg¹ · min¹) compared with Sal. The absence of an increase in epinephrine markedly attenuated these changes (glucose and R_a were 140 ± 6 mg/dl and 2.7 ± 0.4 mg · kg¹ · min¹, respectively). Only 25% of the blunted rise in R_a could be accounted for by an attenuation of the rise in net hepatic gluconeogenic precursor uptake (0.9 ± 0.1, 1.5 ± 0.1, and 1.1 ± 0.2 mg · kg¹ · min¹ for Sal, SHI, and SHIEpi, respectively). The absence of an increase in norepinephrine did not blunt the rise in arterial glucose levels, R_a, or net hepatic gluconeogenic precursor uptake (they rose to 195 ± 21 mg/dl, 3.7 ± 0.5 mg · kg¹ · min¹, and 1.7 ± 0.2 mg · kg¹ · min¹, respectively). In summary, during chronic SHI, the rise in epinephrine exerts potent stimulatory effects on glucose production principally by enhancing hepatic glycogenolysis, although the rise in circulating norepinephrine has minimal effects.