Abnormalities in lipoprotein metabolism are common in uremic patients and may represent an additional risk factor for the development of atherosclerosis. Despite the frequent occurrence of lipoprotein abnormalities, the role of various serum toxins and subfractions that accumulate in uremic patients on lipoprotein metabolism is not clearly understood. This study addressed the role of uremic toxins on lipoprotein metabolism by examining the effect of a 500 to 2,000-d subfraction obtained from the serum of uremic and control subjects on the synthesis of apolipoprotein (apo) A-I in a human hepatoma cell line (Hep-G2). Serum subfractions obtained from uremic patients inhibited apo A-I synthesis and secretion by Hep-G2 cells in a dose-dependent manner as measured by (3H)leucine incorporation into apo A-I, immunoprecipitation, and ELISA. The uremic serum subfraction decreased the mRNA expression for apo A-I in Hep-G2 cells when compared with controls. These observations suggest that a component of uremic serum can have the potential to inhibit hepatic apo A-I synthesis and may adversely influence high-density lipoprotein metabolism, thus increasing the risk for the development of atherosclerotic vascular complications in uremic patients.