The effect of recombinant interferon α 2a (rIFN-α2a) on serum lipoprotein metabolism was assessed in 39 patients with chronic viral hepatitis C. rIFN-α2a was administered intramuscularly at a dose of 9 x 106 U/d for 2 weeks and then for 3 times a week over 6 months. The serum cholesterol concentration significantly decreased one week after rIFN-α;2a administration. Approximately 67% of this decrease was attributed to the reduction of high-density lipoprotein (HDL)-cholesterol; a decrease in HDL2-cholesterol was more evident. By contrast, serum triglyceride levels, largely derived from very-low density lipoprotein (VLDL), significantly increased following rIFN-α2a treatment. Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities in the postheparin plasma were reduced by 75.7% and by 79.4%, respectively, and decreases in plasma cholesteryl ester transfer protein (CETP) activity and its protein mass were also observed. However, prothrombin time was ameliorated by rIFN-α2a, suggesting that the decrease in LPL, HTGL, and CETP activities may not be due to a reduction in protein synthesis by the liver. Simple correlation analysis demonstrated that the changes in LPL activity before and after 2 weeks of treatment with rIFN-α2a showed a significant negative correlation with changes in serum triglyceride and VLDL-triglyceride and a positive correlation with changes in HDL-cholesterol and HDL2-cholesterol. These results suggest a major contribution of reduced LPL activity with regard to the lipoprotein disorders. In conclusion, rIFN-α2a treatment on patients with chronic hepatitis C causes marked changes in serum lipoprotein metabolism associated with decreases in LPL, HTGL, and CETP activities.