OBJECTIVE: We examined whether affect ratings predicted regional cerebral responses to high and low-calorie foods. METHOD: Thirteen normal-weight adult women viewed photographs of high and low-calorie foods while undergoing functional magnetic resonance imaging (fMRI). Regression analysis was used to predict regional activation from positive and negative affect scores. RESULTS: Positive and negative affect had different effects on several important appetite-related regions depending on the calorie content of the food images. When viewing high-calorie foods, positive affect was associated with increased activity in satiety-related regions of the lateral orbitofrontal cortex, but when viewing low-calorie foods, positive affect was associated with increased activity in hunger-related regions including the medial orbitofrontal and insular cortex. The opposite pattern of activity was observed for negative affect. CONCLUSION: These findings suggest a neurobiologic substrate that may be involved in the commonly reported increase in cravings for calorie-dense foods during heightened negative emotions.