Weight loss and malnutrition are common features in patients with Crohn’s disease. This study was designed to evaluate diet-induced thermogenesis and substrate oxidation in patients with Crohn’s disease. Twenty-three patients (17 women, 6 men; age 34 ± 2 y) and 17 healthy control subjects (13 women, 4 men; age 36 ± 3 y) were studied. Resting energy expenditure and fasting substrate oxidation were measured by indirect calorimetry in the morning after an overnight fast. After a standard homogenized test meal (10 kcal/kg), indirect calorimetry was performed every 30 min for 3 h to measure the diet-induced thermogenesis and the postprandial substrate oxidation. In the fasting state, resting energy expenditure was significantly higher in patients than in control subjects (1433 ± 43 versus 1279 ± 53 kcal/24 h). Lipid oxidation was higher in patients with Crohn’s disease than in control subjects (1.17 ± 0.07 versus 0.61 ± 0.11 mg · kg −1 · min −1, P < 0.01). Postprandially, diet-induced thermogenesis was significantly lower in patients with Crohn’s disease than in control subjects (4.6% ± 0.5 versus 6.3% ± 0.5 of energy intake, P < 0.01). Lipid oxidation was significantly higher in patients with Crohn’s disease than in control subjects (0.78 ± 0.05 versus 0.56 ± 0.08 mg · kg −1 · min −1, P < 0.05), and glucose oxidation was lower in patients with Crohn’s disease than in control subjects. In patients with Crohn’s disease, lipid oxidation positively correlates with the disease activity evaluated by the Crohn’s Disease Activity Index ( r = 0.48, P = 0.02) but not with the use of corticosteroids or the nutritional state. In patients with active Crohn’s disease (Crohn’s Disease Activity Index >150), fasting and postprandial lipid oxidation was significantly higher than in patients with inactive Crohn’s disease ( P < 0.05). In conclusion, patients with Crohn’s disease have increased fat oxidation, which correlates with disease activity and this may explain the reduced fat stores in patients with Crohn’s disease.