Background: Research into the excessive eating behaviour associated with Prader-Willi syndrome (PWS) to date has focused on homeostatic and behavioural investigations. The aim of this study was to examine the role of the reward system in such eating behaviour, in terms of both the pattern of food preferences and the neural substrates of incentive in the amygdala and orbitofrontal cortex (OFC). Method: Participants with PWS (n=18) were given a food preference interview to examine food preferences and to inform the food-related incentive task to be conducted during the neuroimaging. Thirteen individuals with PWS took part in the positron emission tomography (PET) study, the design of which was based on a previous study of non-obese, non-PWS controls. For the task, participants were asked to consider photographs of food and to choose the food they would most like to eat in two conditions, one of high and one of low incentive foods, tailored to each participant's preferences. For comparison of the food preference data, 12 non-PWS individuals were given one part of the interview. Results: Individuals with PWS expressed relative liking of different foods and showed preferences that were consistent over time, particularly for sweet foods. The participants with PWS did give the foods in the high incentive condition a significantly higher incentive value than the foods in the low incentive condition. However, activation of the amygdala and medial OFC was not associated with the prospect of highly valued foods as predicted in those with PWS. Conclusions: It would appear that incentive motivation alone plays a less powerful role in individuals with PWS than in those without the syndrome. This is likely to be due to the overriding intrinsic drive to eat because of a lack of satiety in those with PWS, and the impact of this on activity in the incentive processing regions of the brain. Activity in such reward areas may not then function to guide behaviour selectively towards the consumption of high preference foods.