To examine whether escitalopram enhances net hepatic glucose uptake during a hyperinsulinemic hyperglycemic clamp, studies were performed in conscious 42-h-fasted dogs. The experimental period was divided into P1 (0–90 min) and P2 (90–270 min). During P1 and P2 somatostatin (to inhibit insulin and glucagon secretion), 4× basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (2× hepatic glucose load) were infused. Saline was infused intraportally during P1 in all groups. In one group saline infusion was continued in P2 (SAL, n=11), while escitalopram was infused intraportally at 2 μg/kg/min (L-ESC, n=6) or 8 μg/kg/min (H-ESC, n=7) during P2 in two other groups. The arterial insulin concentrations rose ~four fold (to 123±8, 146±13 and 148±15 pmol/L) while glucagon concentrations remained basal (41±3, 44±9 and 40±3 ng/L) in all groups. The hepatic glucose load averaged 216±13, 223±19 and 202±12 μmol/kg/min during the entire experimental period (P1 and P2) in the SAL, L-ESC and H-ESC groups, respectively. Net hepatic glucose uptake was 11.6±1.4, 10.1±0.9 and 10.4±2.3 μmol/kg/min in P1 and averaged 16.9±1.5, 15.7±1.3 and 22.6±3.7 (P<0.05) in the SAL, L-ESC and H-ESC groups, respectively during the last hour of P2 (210–270 min). Net hepatic carbon retention (glycogen storage) was 15.4±1.3, 14.9±0.6 and 20.9±2.6 (P<0.05) µmol/kg/min in SAL, L-ESC and H-ESC respectively during the last hour of P2. Escitalopram enhanced net hepatic glucose uptake and hepatic glycogen deposition, showing that it can improve hepatic glucose clearance under hyperinsulinemic hyperglycemic conditions. Its use in individuals with diabetes may, therefore, result in improved glycemic control.