The increase in VLDL TAG concentration after ingestion of a high-fructose diet is more pronounced in men than in pre-menopausal women. We hypothesised that this may be due to a lower fructose-induced stimulation of de novo lipogenesis (DNL) in pre-menopausal women. To evaluate this hypothesis, nine healthy male and nine healthy female subjects were studied after ingestion of oral loads of fructose enriched with 13 C 6 fructose. Incorporation of 13 C into breath CO 2 , plasma glucose and plasma VLDL palmitate was monitored to evaluate total fructose oxidation, gluconeogenesis and hepatic DNL, respectively. Substrate oxidation was assessed by indirect calorimetry. After 13 C fructose ingestion, 44·0 (SD 3·2) % of labelled carbons were recovered in plasma glucose in males v. 41·9 (SD 2·3) % in females (NS), and 42·9 (SD 3·7) % of labelled carbons were recovered in breath CO 2 in males v. 43·0 (SD 4·5) % in females (NS), indicating similar gluconeogenesis from fructose and total fructose oxidation in males and females. The area under the curve for 13 C VLDL palmitate tracer-to-tracee ratio was four times lower in females (P,0·05), indicating a lower DNL. Furthermore, lipid oxidation was significantly suppressed in males (by 16·4 (SD 5·2), P, 0·05), but it was not suppressed in females (2 1·3 (SD 4·7) %). These results support the hypothesis that females may be protected against fructose-induced hypertriglyceridaemia because of a lower stimulation of DNL and a lower suppression of lipid oxidation. De novo lipogenesis: VLDL TAG: Endogenous glucose productionThe metabolic effects of a high-fructose diet have been widely studied in both animals and human subjects (1) . High-fructose diet is associated with the development of at least two features of the metabolic syndrome, i.e. insulin resistance and increased plasma VLDL TAG. The latter may in turn be associated with an increased production of small, dense LDL particle with high atherogenic potential (2,3) . It has been reported by several authors that a high-fructose diet increases plasma TAG less and does not reduce insulin sensitivity in both pre-menopausal women and female rodents compared with males (4 -11) . This may be due to a sex-specific difference in either fructose metabolism or adaptations to chronic fructose overfeeding. To our knowledge, whether the metabolism of an acute fructose load differs in females and males has not been specifically assessed. Fructose disposal relies mainly on the stimulation of carbohydrate oxidation (fructose oxidation in splanchnic organs and indirect oxidation of glucose and lactate synthesised from the fructose), gluconeogenesis, hepatic glycogen storage and hepatic de novo lipogenesis (DNL). The latter, although a quantitatively minor pathway for fructose disposal, may be closely linked to hepatic VLDL TAG production and synthesis of intra-hepatic lipids. Therefore, we hypothesised that fructose-induced stimulation of DNL may be blunted in pre-menopausal women.To evaluate this hypothesis, we compared the metabolic fate of i...