Serum total sialic acid (S-TSA) is a recently identified risk marker for atherosclerosis and cardiovascular mortality. The purpose of this study was to evaluate the influence of three sialic acid rich glycoproteins (orosomucoid, haptoglobin, and alpha1-antitrypsin) on the relationship between S-TSA and carotid atherosclerosis. The mean S-TSA was 0.045 g/l higher among cases than controls (P<0.001) in 310 45-64 year-old male and female pairs of carotid atherosclerosis cases and disease-free controls from the Atherosclerosis Risk in Communities (ARIC) Study. Also mean serum levels of the glycoproteins were significantly higher in cases compared to controls. In a conditional multiple logistic regression model with the glycoproteins as independent variables, orosomucoid was correlated most strongly with case control status. However, when incorporated into the mathematical model, S-TSA not only contributed additional information as to the risk of atherosclerosis; none of the three glycoproteins contributed further once S-TSA had been accounted for. Thus, some other source of serum sialic acid or variations in the degree of sialylation of glycoproteins may be essential for understanding the relation between S-TSA and atherosclerosis.