Increases in consumption of sugar-sweeteners are linked to obesity, diabetes and cardiovascular disease. Studies by our group and others suggest that the fructose component of sugar-sweeteners may act centrally to promote overeating behavior. Using functional magnetic resonance imaging (fMRI), we previously demonstrated that, unlike glucose, fructose ingestion failed to reduce neuronal activity in brain appetite and reward regions and failed to increase satiety in normal-weight adults. The objective of this study was to test the hypothesis that fructose compared to glucose ingestion would cause greater food-cue reactivity in brain reward areas and greater hunger, and that these differential effects would be heightened in obese compared to lean individuals. This study is part of a larger ongoing double-blinded, random-order crossover study on brain, hormone and appetitive responses to acute consumption of drinks containing 75 grams (300kcal) fructose or an equivalent dose of glucose. fMRI scans were performed using a 3-Tesla scanner on 13 participants, 5 obese (3 female,2 male; age 22±2, BMI 37±3.8) and 8 lean (3 female,5 male; age 21±2, BMI 22.8±1.7). Scanning was performed while participants viewed images of high-calorie food pictures and non-food items using a block design. Appetite scales were obtained before and 60 min after drink ingestion. Blood-oxygen level dependent (BOLD) sequences were used to measure brain responses to food and non-food cues after drink ingestion. Paired-t tests were performed to examine drink effects on BOLD responses to high-calorie food vs. non-food cues and hunger responses. Obese vs. lean comparison of drink effects were analyzed using independent samples T-tests. In the total group, fructose vs. glucose ingestion resulted in greater activation of the amygdala (9.1±4, p=.045) and the nucleus accumbens (11.4±6, p=.07), brain regions that mediate reward and pleasure. There were no significant differences in baseline hunger ratings between sessions. However, hunger ratings were significantly greater after consumption of fructose compared to glucose (1.9±0.6, p=.011). Body mass index (BMI) group interactions were seen with drink condition. Amygdala activation was significantly greater after fructose vs. glucose ingestion in the obese group (t(1,4)=4.406, p=0.01), but not the lean group (t(1,7)=0.754, p=0.48). Ratings of hunger tended to be higher after fructose vs. glucose ingestion in the obese compared to the lean group but the differences were not statistically significant with this sample size (p=0.15). In conclusion, these results demonstrate that acute consumption of fructose compared to glucose results in greater brain reward activation to high-calorie food cues and increased hunger. These disparate responses to fructose vs. glucose ingestion were heightened in obese individuals and may play a role in promoting overeating behavior.