Intraportal serotonin infusion enhances net hepatic glucose uptake (NHGU) during glucose infusion but blunts nonhepatic glucose uptake and can cause gastrointestinal (GI) discomfort and diarrhea at high doses. Whether the serotonin precursor 5-hydroxytryptophan (5-HTP) could enhance NHGU without GI side effects during glucose infusion was examined in 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; 0-270 min) periods. During EXP, somatostatin, 4-fold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. In one group of dogs (HTP, n=6), saline was infused intraportally from 0-90 min (P1), and 5-HTP was infused intraportally at 10, 20, and 40 µg^.kg^-1.min^-1 from 90-150 (P2), 150-210 (P3), and 210-270 (P4) min, respectively. In the other group (SAL, n=7), saline was infused intraportally from 0-270 min. NHGU in SAL was 14.8±1.9, 18.5±2.3, 16.3±1.4, and 19.7±1.6 µmol^.kg^-1.min^-1 in P1-4, respectively, while NHGU in HTP averaged 16.4±2.6, 18.5±1.4, 20.8±2.0, and 27.6±2.6^* µmol^.kg^-1.min^-1 (^*P<0.05 vs SAL). Nonhepatic glucose uptake (µmol^.kg^-1.min^-1) in SAL was 30.2±4.3, 36.8±5.8, 44.3±5.8, and 54.6±11.8 during P1-4, respectively, while in HTP the corresponding values were 26.3±6.8, 44.9±10.1, 47.5±11.7, and 51.4±13.2 (NS between groups). Intraportal 5-HTP enhances NHGU without significantly altering nonhepatic glucose uptake or causing GI side effects, raising the possibility that a related agent might have a role in reducing postprandial hyperglycemia.