The effect of para-aminosalicylic acid-C (PAS-C, 8 g/day) on lipid metabolism was studied on a metabolic ward in nine subjects with primary endogenous hypertriglyceridemia. During 2 wk on a basal isocaloric liquid formula diet (40% fat, 45% carbohydrate), PAS-C reduced plasma triglyceride (-41.9 +/- 18.9%, p less than .01, -x +/- SD), cholesterol (-22.8 +/- 12.9%, p less than .005), and a very low density lipoprotein triglyceride (p less than .001) and cholesterol (p less than .01) levels without changing the cholesterol content of low density or high density lipoproteins. Similar effects occurred on a fat-free, 85% carbohydrate diet. Decreases in very low density lipoproteins correlated with changes in both total triglyceride (r = .99, p less than .01) and cholesterol (r = .70, p less than .05). Treatment with PAS-C reduced the plasma triglyceride removal rate related to lipoprotein lipase (-14.6 +/- 14.1%, p less than .02), but did not alter plasma postheparin lipolytic activity or the apparent Km for substrate-enzyme interaction. Kinetic data obtained during the prolonged heparin infusion fit the linearized Michaelis-Menten model for subjects with endogenous hypertriglyceridemia. The reduction in the plasma triglyceride concentration during PAS-C treatment was a function of the decrease in triglyceride removal rate (r = .74, p less than .025) without alternation in the maximal removal capacity related to lipoprotein lipase. This suggests that under the steady state conditions of these studies, the decrease in plasma triglyceride concentration was due to a reduction in endogenous triglyceride production. Free fatty acid metabolism, glucose homeostasis, fat absorption, and thyroid function did not change. These results suggest that PAS-C lowers plasma triglyceride and cholesterol levels in hypertriglyceridemic subjects reducing endogenous very low density lipoprotein production and/or secretion into the circulation.