Seventeen normotensive, premenopausal women were treated with the 5-hydroxytryptamine-reuptake inhibitor dexfenfluramine 30 mg per day, for 4 days in a randomised double-blind, cross-over, placebo controlled trial. Energy intake was held constant during the study as the aim was to study the endocrine and metabolic effects of dexfenfluramine dissociated from its weight-lowering properties. Body weight, blood glucose, plasma insulin, cholesterol triglycerides and C-peptide after an overnight fast and during an oral load of 100 g glucose did not change after dexfenfluramine compared to placebo. Supine and standing systolic and diastolic blood pressures were significantly decreased, while heart rate remained unchanged. Plasma noradrenaline and plasma renin were markedly reduced by dexfenfluramine, and cortisol, beta-endorphin and thyroid hormones were not changed. Thus, dexfenfluramine has a significant hypotensive effect in normotensive, obese women after 4 days of treatment, independent of a negative energy balance. This was associated with decreased circulating plasma noradrenaline, indicating decreased sympathetic nerve activity. Dexfenfluramine may be a candidate drug for longer-term trials in the treatment of primary hypertension associated with obesity.