Whether hyperinsulinemia is required for stimulation of net hepatic glucose uptake (NHGU) by a selective serotonin reuptake inhibitor (SSRI) was examined in 4 groups of conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-³H]glucose) techniques. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-240 min) periods. During EXP, somatostatin, intraportal insulin (at basal [ins groups] or 4-fold basal [INS groups] rates), basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. In the FLUV-ins (n=7) and FLUV-INS (n=6) groups, saline was infused intraportally from 0-90 min (P1), and fluvoxamine was infused intraportally at 2 µg^.kg^{-1 .}min^-1 from 90-240 min (P2) min. SAL-ins (n=9) and SAL-INS (n=8) received intraportal saline in P1 and P2. NHGU (µmol^.kg^{-1 .}min^-1) during P2 was 8.4±1.4 and 6.9±2.3 in SAL-ins and FLUV-ins, respectively (NS), and 13.3±2.2 and 20.9±3.1 (P<0.05) in SAL-INS and FLUV-INS. Unidirectional (tracer-determined) hepatic glucose uptake was 2-fold greater (P<0.05) in FLUV-INS vs SAL-INS. Net hepatic carbon retention during P2 was significantly greater in FLUV-INS vs SAL-INS (18.5±2.7 vs 12.2±1.9 µmol^.kg^{-1 .}min^-1). Nonhepatic glucose uptake was reduced in FLUV-INS vs SAL-INS (20.0±1.3 vs 38.4±5.4 µmol^.kg^{-1 .}min^-1, P<0.05). Intraportal fluvoxamine enhanced NHGU and net hepatic carbon retention in the presence of hyperinsulinemia but not euinsulinemia, suggesting that hepatocyte-targeted SSRIs may reduce postprandial hyperglycemia.