To investigate whether a serotoninergic drug such as dexfenfluramine (dF) may have some beneficial effects on energy expenditure (EE) during therapeutic weight reduction, a 3-month study was conducted in a double-blind, placebo-controlled trial. Thirty-two obese, premenopausal women received either dF or placebo (P) in addition to a very-low-calorie diet (VLCD) prescription. All patients started--when hospitalized at the metabolic ward--with a 500-kcal regimen and fulfilled the 3-month trial on a +/- 760-kcal protein-sparing modified fast. Although not statistically significant, women receiving dF lost more weight (16.0 +/- 1.4 v 12.8 +/- 1.3 kg, P = .111) over the 3-month study period. Resting metabolic rate (RMR) decreased significantly by 5% in the dF group (4.79 to 4.53 kJ/min) and by 9% in the P group (5.09 to 4.63 kJ/min). When expressed per kilogram body weight, RMR significantly increased from 0.050 to 0.057 kJ/min/kg in the dF group (P < .001), versus 0.053 to 0.056 in the P group (NS). When expressed per kilogram fat-free mass (FFM), RMR remained stable in the dF group, whereas it significantly decreased in the P group (P = .024). No significant differences could be found between groups. Glucose-induced thermogenesis (GIT), expressed as percent increase above RMR, did not show significant differences between groups. When expressed per kilogram body weight, mean GIT increased in the dF group from 0.14% to 0.16% above RMR, with a significant decrease from 0.15% to 0.13% in the P group. Only during the first hour did GIT per kilogram body weight significantly (P = .038) increase in the dF group during the outpatient period (between day 16 and day 90). These results show that a serotoninergic drug seems capable of limiting the weight reduction-associated decrease in RMR and dietary-induced thermogenesis (DIT), certainly when expressed on a per-kilogram-weight basis.