We are continuously exposed to food and during the day we make many food choices. These choices play an important role in the regulation of food intake and thereby in weight management. Therefore, it is important to obtain more insight into the mechanisms that underlie these choices. While several food choice functional MRI (fMRI) studies have been conducted, the effect of energy content on neural responses during food choice has, to our knowledge, not been investigated before. Our objective was to examine brain responses during food choices between equally liked high- and low-calorie foods in the absence of hunger. During a 10-min fMRI scan 19 normal weight volunteers performed a forced-choice task. Food pairs were matched on individual liking but differed in perceived and actual caloric content (high-low). Food choice compared with non-food choice elicited stronger unilateral activation in the left insula, superior temporal sulcus, posterior cingulate gyrus and (pre)cuneus. This suggests that the food stimuli were more salient despite subject's low motivation to eat. The right superior temporal sulcus (STS) was the only region that exhibited greater activation for high versus low calorie food choices between foods matched on liking. Together with previous studies, this suggests that STS activation during food evaluation and choice may reflect the food's biological relevance independent of food preference. This novel finding warrants further research into the effects of hunger state and weight status on STS, which may provide a marker of biological relevance.