Elevated plasma viscosity is a predictor of atherosclerotic vascular disease and is a potential mechanism by which hypertriglyceridemia increases cardiovascular risk. Previous studies of plasma viscosity reduction in hypertriglyceridemic patients used medications that lowered both triglyceride and fibrinogen levels. Because fibrinogen is a major determinant of viscosity, it is unclear whether triglyceride reduction alone is sufficient to reduce plasma viscosity. The purpose of this study was to determine whether triglyceride-lowering therapy reduces plasma viscosity. This was a prospective study of 24 adult patients with severe hypertriglyceridemia (> or = 5.67 mmol/l). Fasting lipid, total serum protein, fibrinogen, plasma viscosity and serum viscosity levels were measured before and after therapy with 1200 mg/d of gemfibrozil. Triglyceride levels decreased by 70% (P < 0.001). Mean plasma and serum viscosity levels decreased by 0.082 mPa/s (P = 0.003) and 0.086 mPa/s (P = 0.013), respectively. Fibrinogen levels did not change significantly. Triglyceride-lowering therapy reduced plasma and serum viscosity without changes in fibrinogen levels. Since serum samples are deplete of fibrinogen, the serum viscosity reduction observed is corroborative evidence for an independent effect of triglyceride-lowering therapy on plasma viscosity. This observation provides a physiological rationale for triglyceride-lowering therapy in patients at risk for atherosclerotic vascular disease, the chylomicronemia syndrome and pancreatitis.