BACKGROUND: Animal studies suggest that liver weight is directly related to hepatic very low-density lipoprotein-triglyceride (VLDL-TG) secretion, independently of body size. This relationship has never been examined in humans. MATERIALS AND METHODS: We measured VLDL-TG secretion rate by using stable isotope-labelled tracers in 21 healthy, non-obese men (age: 25 +/- 3 years; body mass index: 24.8 +/- 1.6 kg m(-2)), and evaluated the relationship between VLDL-TG secretion and indices of total and regional adiposity (body mass index, total body fat, trunk fat), metabolic parameters (free fatty acid, glucose, and insulin concentrations, homeostasis model assessment index of insulin resistance, resting energy expenditure), and estimated liver weight. RESULTS: Correlation analysis showed that estimated liver weight was positively associated with total VLDL-TG secretion rate (r = 0.722, P < 0.001), VLDL-TG secretion rate per liter of plasma (r = 0.562, P = 0.008), VLDL-TG secretion rate per kilogram of body weight (r = 0.555, P = 0.009), and VLDL-TG secretion rate per kilogram of liver weight (r = 0.620, P = 0.003). In multiple regression analysis, estimated liver weight was the only significant predictor of VLDL-TG secretion rate regardless of units of expression, explaining 31-52% of total variance; none of the metabolic parameters and indices of body fatness entered the regression models. CONCLUSIONS: We conclude that estimated liver weight is directly related to hepatic VLDL-TG secretion rate in healthy non-obese men; this relationship is likely not mediated by interindividual variation in body size.