Technical Abstract: Objective: In animals, intracerebroventricular glucose and fructose have opposing effects on appetite and weight regulation. In humans, functional brain magnetic resonance imaging (fMRI) studies during carbohydrate ingestion suggest that glucose may regulate HT signaling but are potentially confounded by upper alimentary track neural inputs and changes in gut hormone secretion during ingestion. We therefore sought to determine the brain response to intravenously(IV)infused carbohydrates, and if this response differed between glucose and fructose,in humans. Methods: Nine healthy, normal weight subjects underwent blood oxygenation level dependent(BOLD) fMRI measurements during either IV glucose (0.3 mg/kg), fructose (0.3 mg/kg), or saline, administered over 2-minutes in a randomized, double-blind, crossover study. Blood was sampled every 5-minutes during a baseline period and following infusion for 60-minutes total for glucose, fructose, lactate, and insulin levels. Results: No significant brain BOLD signal changes were detected in response to IV saline. BOLD signal in the cortical control areas increased during glucose infusion (p = 0.002), corresponding with increased plasma glucose and insulin levels. In contrast, BOLD signal decreased in the cortical control areas during fructose infusion (p = 0.006), corresponding with increases of plasma fructose and lactate. Neither glucose nor fructose infusions significantly altered BOLD signal in the HT. Conclusion: In normal weight humans, cortical responses as assessed by BOLD fMRI to infused glucose are opposite to those of fructose. Differential brain responses to these sugars and their metabolites may provide insight into the neurologic basis for dysregulation of food intake during high dietary fructose intake.