Background: Protein is indispensable in the human diet, and its intake appears tightly regulated. The role of sensory attributes of foods in protein intake regulation is far from clear. Objective: We investigated the effect of human protein status on neural responses to different food cues with the use of functional magnetic resonance imaging (fMRI). The food cues varied by taste category (sweet compared with savory) and protein content (low compared with high). In addition, food preferences and intakes were measured. Design: We used a randomized crossover design whereby 23 healthy women [mean SD age: 22 +/- 2 y; mean +/- SD body mass index (in kg/m(2)): 22.5 +/- 1.8] followed two 16-d fully controlled dietary interventions involving consumption of either a low-protein diet (0.6 g protein center dot kg body weight(-1) center dot d(-1), similar to 7% of energy derived from protein, approximately half the normal protein intake) or a high-protein diet (2.2 g protein center dot kg body weight(-1) center dot d(-1), similar to 25% of energy, approximately twice the normal intake). On the last day of the interventions, blood oxygen level-dependent (BOLD) responses to odor and visual food cues were measured by using fMRI. The 2 interventions were followed by a 1 -d ad libitum phase, during which a large array of food items was available and preference and intake were measured. Results: When exposed to food cues (relative to the control condition), the BOLD response was higher in reward-related areas (orbitofrontal cortex, striatum) in a low-protein state than in a high-protein state. Specifically, BOLD was higher in the inferior orbitofrontal cortex in response to savory food cues. In contrast, the protein content of the food cues did not modulate the BOLD response. A low protein state also increased preferences for savory food cues and increased protein intake in the ad libitum phase as compared with a high-protein state. Conclusions: Protein status modulates brain responses in reward regions to savory food cues. These novel findings suggest that dietary protein status affects taste category preferences, which could play an important role in the regulation of protein intake in humans. This trial was registered at www.trialregister.nl/trialreg/admin/rctview.asp?TC=3288 as NTR3288.