Effects of suboptimal and adequate vitamin C, with varying dietary fat saturation, on hepatic cholesterol and plasma lipoprotein concentrations and metabolism were studied in guinea pigs fed 15% (wt/wt) fat/0.04% cholesterol diets. Fat mixtures were either 49% saturated (SFA) (24% lauric acid) or 53% polyunsaturated fatty acid (PUFA) linoleic acid with vitamin C at 50 (suboptimal) or 500 (adequate) mg/kg diet. Guinea pigs fed suboptimal vitamin C had 15% lower hepatic active 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and 25% lower low-density lipoprotein (LDL; apolipoprotein [apo] B/E) receptor number, 20% higher acyl-CoA:cholesterol acyltransferase (ACAT) activity, 28% higher triacylglycerol (TAG) and cholesteryl ester concentrations, and increased very-low-density lipopoprotein (VLDL) apo B secretion rates in comparison to animals fed adequate vitamin C. Intake of suboptimal vitamin C lowered plasma high-density lipoprotein (HDL) cholesterol concentrations by 45% and increased plasma TAG, total and VLDL/LDL cholesterol, and cholesteryl ester transfer protein (CETP) activity by 40%, 50%, and 30%, respectively. The hyperlipidemic effects of suboptimal vitamin C were more pronounced with intake of the SFA diet. These data demonstrate that low vitamin C intake results in a pattern of changes in whole-body cholesterol and lipoprotein metabolism that are related to increased risk of cardiovascular disease (CVD).