Objective and Design To investigate the association between the severity of sepsis and changes in sialylation of serum proteins we have conducted a single center pilot study. Subjects and Methods Sialylation of transferrin (with enzyme-linked lectin assay-ELLA) and total serum proteins (with colorimetric assay) as well as serum iron and transferrin levels were measured in 27 patients with sepsis through the first eight days of the disease. Results Total serum sialylation increased in the first two days, transferrin sialylation decreased, while serum iron and transferrin fell. Patients who developed severe sepsis had either a small or marked change in transferrin sialylation while in patients with mild sepsis sialylation decreased moderately. Conclusion We hypothesize that the change in transferrin sialylation could be a reflection of the intensity of inflammatory response which is insufficient if under-expressed and detrimental if over-expressed. This new feature is a potential marker of sepsis severity early in the disease.