Hypoalbuminemia is accompanied by hypercholesterolemia in both nephrotic syndrome and hereditary analbuminemia. Hypercholesterolemia is more severe in the female than in the male Nagase analbuminemic rats (NAR). The gender difference in plasma cholesterol diminishes ovariectomy (OVX) and reappears by estrogen replacement in the NAR. The molecular mechanism responsible for the gender difference in severity of hypercholesterolemia in NAR is not known and was investigated here. To this end, hepatic HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), cholesterol 7-hydroxylase (the rate-limiting enzyme in cholesterol catabolism to bile acids) and LDL receptor expressions were determined in male, female and OVX female NAR and Sprague-Dawley (SD) control rats. Plasma cholesterol (total and lipoprotein fractions), triglycerides and hepatic HMG-CoA reductase activity were significantly greater in both female and male NAR than in the corresponding SD rats. This was coupled with a compensatory upregulation of hepatic cholesterol 7-hydroxylase in both male and female NAR compared to the corresponding SD controls. Hepatic LDL receptor abundance in the male NAR was similar to that found in the male SD rats but significantly reduced in the female NAR. OVX resulted in significant reductions of plasma cholesterol to values intermediate between female and male NAR. Similarly plasma triglyceride was markedly lowered by OVX in the NAR. This was coupled with a significant rise in hepatic cholesterol 7-hydroxylase and a modest increase in hepatic LDL receptor. In contrast, OVX resulted in mild elevation of plasma cholesterol and no significant changes in total hepatic HMG-CoA reductase, cholesterol 7-hydroxylase or LDL receptor abundance in the female SD rats. Thus, hypercholesterolemia in hereditary analbuminemia is associated with and primarily due to increased cholesterol biosynthetic capacity. This is compounded by a mild LDL receptor deficiency in the female NAR. The greater severity of hypercholesterolemia in the female than in the male NAR appears to be, in part, due to the constrained compensatory upregulation of cholesterol 7-hydroxylase and LDL receptor deficiency.