BACKGROUND Isocaloric manipulation of carbohydrate or fat intake could alter subsequent ad libitum food intake. METHODS In a controlled inpatient study, we investigated whether isocaloric manipulation of carbohydrate or fat would alter subsequent ad libitum energy intake. Eighteen non-diabetic subjects (age range 19-53 years.; 15 M/3F; % body fat 38.5 ± 9.1 (mean ± SD)) were fed for 3 days an isocaloric high-carbohydrate diet (HC; 60% carbohydrate, 20% fat, 20% protein) and a high-fat diet (HF; 50% fat, 30% carbohydrate, 20% protein) in random order each followed by 3 days of ad libitum food intake. RESULTS There were no differences in mean daily energy intake (EI) following each diet (HC vs. HF: 4,811 ± 1,190 vs. 4,823 ± 1,238 kcal/d; P = 0.7) or in the percent of weight maintenance energy needs (%EN-WM; 173 ± 41 vs. 173 ± 46%, P = 0.5). However, the individual difference in EI between the HF versus HC diet (ΔEI) both on day one and over the 3 days of each ad libitum period was negatively associated with % body fat (%BF) and waist circumference (day 1: ΔEI vs. %BF, r = -0.49, P = 0.04; mean day 1-3 kcal ΔEI vs. %BF, r = -0.66, P = 0.003, and ΔEI vs. waist, r = -0.65, P = 0.004). CONCLUSIONS A short-term isocaloric HC diet did not result in overall lower EI compared with a HF diet in the same individuals. However, we did find that increasing body fat was associated with less decline in EI following the HC versus HF diet indicating that increasing adiposity is associated with altered regulation of EI in response to macronutrient changes.