BACKGROUND: Flexibility of food reward-related brain signaling (FRS) between food and nonfood stimuli may differ between overweight and normal-weight subjects and depend on a fasted or satiated state. OBJECTIVE: The objective was to assess this flexibility in response to visual food and nonfood cues. DESIGN: Twenty normal-weight [BMI (in kg/m(2)) = 22.7 +/- 0.2; age = 22.4 +/- 0.4 y] and 20 overweight (BMI = 28.1 +/- 0.3; age = 24.0 +/- 0.7 y) participants completed 2 fMRI scans. Subjects arrived in a fasted state and consumed a breakfast consisting of 20% of subject-specific energy requirements between 2 successive scans. A block paradigm and a food > nonfood contrast was used to determine FRS. RESULTS: An overall stimulus x condition x subject group effect was observed in the anterior cingulate cortex (ACC) (P < 0.006, F((1,38)) = 9.12) and right putamen (P < 0.006, F((1,38)) = 9.27). In all participants, FRS decreased from the fasted to the satiated state in the cingulate (P < 0.005, t((39)) = 3.15) and right prefrontal cortex (PFC) (P < 0.006, t((39)) = 3.00). In the fasted state, they showed FRS in the PFC (P < 0.004, t((39)) = 3.17), left insula (P < 0.009, t((39)) = 2.95), right insula (P < 0.005, t((39)) = 3.12), cingulate cortex (P < 0.004, t((39)) = 3.21), and thalamus (P < 0.006, t((39)) = 2.96). In the satiated state, FRS was limited to the left insula (P < 0.005, t((39)) = 3.21), right insula (P < 0.006, t((39)) = 3.04), and cingulate cortex (P < 0.005, t((39)) = 3.15). Regarding subject group, in the fasted state FRS in the ACC was more pronounced in overweight than in normal-weight subjects (P < 0.005, F((1,38)) = 9.71), whereas in the satiated state, FRS was less pronounced in overweight than in normal-weight subjects in the ACC (P < 0.006, F((1,38)) = 9.18) and PFC (P < 0.006, F((1,38)) = 8.86), which suggests lower inhibitory control in the overweight. CONCLUSIONS: FRS was higher in the overweight in the satiated state; however, when sufficiently satiated, the overweight showed decreased inhibitory control signalling, which facilitates overeating. This trial was registered in the Dutch clinical trial register as NTR2174.