Objective: The effect of oral glucose-induced release of gastrointestinal hormones on satiety and appetite independently of prevailing plasma glucose excursions is unknown. The objective is to investigate the effect of oral glucose on appetite and satiety sensations as compared to isoglycemic IV glucose infusion (IIGI) in healthy volunteers. Design: A crossover study involving two study days for each participant. Participants: Nineteen healthy participants (6 women, mean age 55.1 [SD 14.2] years; mean body mass index 26.7 [SD 2.2] kg/m²). Interventions: Each participant underwent a 3-h 50-g oral glucose tolerance test (OGTT) and, on a subsequent study day, an IIGI mimicking the glucose excursions from the OGTT. On both study days, appetite and satiety were indicated regularly on visual analog scale (VAS), and blood was drawn regularly for measurement of pancreatic and gut hormones. Primary outcomes: Difference in appetite and satiety sensations during OGTT and IIGI. Results: Circulating concentrations of glucose-dependent insulinotropic polypeptide (P <. 0001), glucagon-like peptide 1 (P <. 0001), insulin (P <. 0001), C-peptide (P <. 0001), and neurotensin (P =. 003) increased significantly during the OGTT as compared to the IIGI, whereas glucagon responses were similarly suppressed (P =. 991). Visual analog scale-assessed ratings of hunger, satiety, fullness, thirst, well-being, and nausea, respectively, were similar during OGTT and IIGI whether assessed as mean 0-3-h values or area under the curves. For both groups, a similar, slow increase in appetite and decrease in satiation were observed. Area under the curve, for prospective food consumption (P =. 049) and overall appetite score (P =. 044) were slightly lower during OGTT compared to IIGI, whereas mean 0-3-h values were statistically similar for prospective food consumption (P =. 053) and overall appetite score (P =. 063). Conclusions: Despite eliciting robust responses of appetite-reducing and/or satiety-promoting gut hormones, we found that oral glucose administration has little or no effect on appetite and satiety as compared to an IIGI, not affecting the release of appetite-modulating hormones.