During chronic total parenteral nutrition (TPN), net hepatic glucose uptake (NHGU) is markedly elevated. However, NHGU is reduced by the presence of an infection. We recently demonstrated that a small, acute (3-h) intraportal fructose infusion can correct the infection-induced impairment in NHGU. The aim of this study was to determine whether the addition of fructose to the TPN persistently enhances NHGU in the presence of an infection. TPN was infused continuously into the inferior vena cava of chronically catheterized dogs for 5 days. On day 3, a bacterial clot was implanted in the peritoneal cavity, and either saline (CON, n = 5) or fructose (+FRUC, 1.0 mg · kg¹ · min¹, n = 6) infusion was included with the TPN. Forty-two hours after the infection was induced, hepatic glucose metabolism was assessed in conscious dogs with arteriovenous and tracer methods. Arterial plasma glucose concentration was lower with chronic fructose infusion (120 ± 4 vs. 131 ± 3 mg/dl, +FRUC vs. CON, P < 0.05); however, NHGU was not enhanced (2.2 ± 0.5 vs. 2.8 ± 0.4 mg · kg¹ · min¹). Acute removal of the fructose infusion dramatically decreased NHGU (2.2 ± 0.5 to 0.2 ± 0.5 mg · kg¹ · min¹), and net hepatic lactate release also fell (1.6 ± 0.3 to 0.5 ± 0.3 mg · kg¹ · min¹). This led to an increase in the arterial plasma glucose (13 ± 3 mg/dl, P < 0.05) and insulin (5 ± 2 µU/ml) concentrations and to a decrease in glucagon (11 ± 3 pg/ml) concentration. In conclusion, the addition of chronic fructose infusion to TPN during infection does not lead to a persistent augmentation of NHGU.