To investigate the mechanism of elevated plasma triglycerides in non-insulin-dependent (type II) diabetes, very-low-density lipoprotein triglyceride (VLDL-TG) metabolism was studied in 10 untreated male Pima Indian diabetics and compared with that of 15 weightmatched male nondiabetic controls. VLDL-TG metabolism was studied using tritiated glycerol as an endogenous precursor of VLDL-TG, and the resultant kinetic data were analyzed using a multicompartmental model, which includes two pathways for VLDL-TG synthesis and a stepwise delipidation process for VLDL catabolism. Pima diabetics had VLDL-TG concentrations approximately 150% those of nondiabetics. Rates of VLDL-TG production in the diabetics were not significantly different from those of controls. On the other hand, the fractional catabolic rate for VLDL-TG was significantly lower in the diabetics compared with the nondiabetics. Other catabolic parameters, such as the fraction of VLDL-TG delipidized at each step and the stepwise delipidation rate, were also decreased in the diabetics. To determine the relationships between the increased triglycerides and determinants of lipid metabolism that are altered in diabetes, insulin and free fatty acid concentrations were also assessed. Basal C-peptide levels in the diabetics during the metabolic study were slightly but not significantly higher than those of the nondiabetics. There was a highly significant correlation in the diabetics between plasma C-peptides and VLDL-TG production, whereas VLDL production in Pima nondiabetics was not related to insulin levels. Free fatty acid levels were not significantly elevated in the Pima diabetics. The data indicate that (1) the rise in VLDL-TG in Pima diabetics was a result of decreased capacity for clearance and (2) the absence of elevated VLDL-TG production may be attributed to the lack of increase in free fatty acids.