The aim of this study was to evaluate the chronic effects of a short-chain fructo-oligosaccharide (FOS)-containing diet on plasma lipids and the activity of fatty acid synthase (FAS) in insulin-resistant rats. Normal male Sprague-Dawley rats, 5 wk old, were randomly assigned to two groups and fed either a sucrose-rich diet (S, 575 g sucrose /kg diet and 140 g lipids/kg diet) or a sucrose-rich diet supplemented with 10 g/100 g short-chain fructo-oligosaccharides (S/FOS). A third reference group (R) was fed a standard nonpurified diet (g/kg, 575 g starch, 50 g fat). After 3 wk the sucrose-fed rats (compared with the R group) were characterized by the following: 1) higher insulin responses after a glucose challenge (P < 0.05); 2) heavier liver (P < 0.001) and retroperitoneal adipose tissue (P < 0.01); 3) hypertriglyceridemia (P < 0.0001) and higher plasma free fatty acids (P < 0.0001); and 4) higher fatty acid synthase activity in the liver but a low activity in the adipose tissue (P < 0.001). The addition of FOS to the diet resulted in 11% lower liver weight than in the S group (P < 0.05) and tended to result in lower adipose tissue weight (P < 0.11). Plasma triglycerides and plasma free fatty acids were lower in S/FOS- than in S-fed rats (P < 0.05). Chylomicrons + VLDL, and intermediate density lipoprotein (IDL) concentrations did not differ between groups, nor was plasma cholesterol influenced by diet. Hepatic FAS activity was lower in S/FOS-fed rats than in the S-fed rats (P < 0.05). In adipose tissue, however, this activity tended to be greater in rats fed S/FOS than in rats fed the S diet (P < 0.07). In conclusion, in a rat model of diet-induced (57.5% sucrose and 14% lipids) insulin resistance, the addition of short-chain FOS prevented some lipid disorders, lowered fatty acid synthase activity in the liver and tended to raise this activity in the adipose tissue. Short-chain FOS, in addition to being a nondigestible sweetener with good bulking capacity, might be useful in the treatment of insulin resistance and hyperlipidemia.