1 To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2 Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post‐dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3 Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136±1509 μg vs 1986±792 μg; 95% CI of difference 926–3374; Pvs 1626±444 μg). 4 Dexfenfluramine AUC was higher in PMs (677±348 μg l−1 h) than EMs (359±250 μg l−1 h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6±42.4 l h−1vs 45.6±19.5 l h−1; 95% CI of difference 1.2–94.7; P−1; PMs 6.60±2.01 l h−1), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5 The apparent nonrenal clearance of dexfenfluramine was substantially lower (P−1) than EMs (87.6±41.2 l h−1). 6 There was a significant inverse correlation (rs=−0.776 95% CI −0.31–−0.94; n=11; P=0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7 PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8 In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.