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Background: Obesity increases the risk of endometrial cancer (EC) and obese EC patients have the highest risk of death among all obesity-associated cancers. However, only two lifestyle interventions targeting this high-risk population have been conducted. In one trial, food disinhibition, as determined by the Three-Factor Eating Questionnaire, decreased post-intervention compared to baseline, suggesting an increase in emotional eating and, potentially, an increase in food related reward. Therefore, we evaluated appetitive behavior using functional magnetic resonance imaging (fMRI) and a visual food task in 8 obese, Stage I/II EC patients before and after a lifestyle intervention (Survivors in Uterine Cancer Empowered by Exercise and a Healthy Diet, SUCCEED), which aimed to improve nutritional and exercise behaviors over 16 group sessions in 6 months using social cognitive theory., Results: Congruent to findings in the general obese population, we found that obese EC patients, at baseline, had increased activation in response to high- vs. low-calorie food cues after eating a meal in brain regions associated with food reward (insula, cingulate gyrus; precentral gyrus; whole brain cluster corrected, p < 0.05). At 6 months post-intervention compared to baseline, we observed decreased activation for the high-calorie vs. non-food contrast, post-meal, in regions involved in food reward and motivation (posterior cingulate, cingulate gyrus, lateral globus pallidus, thalamus; claustrum; whole brain cluster corrected, p < 0.05)., Conclusions: Our preliminary results suggest behavioral lifestyle interventions may help to reduce high-calorie food reward in obese EC survivors who are at a high-risk of death. To our knowledge, this is the first study to demonstrate such changes.