The immunomodulatory activities of four sialic acid-containing milk proteins (κ-casein, glycomacropeptide, lactoferrin, and proteose peptone-3 component) were determined, and the role of sialic acid was evaluated. Two in vitro models were used: murine splenocyte proliferation, where the effect on LPS-, Con A-, and PHA-stimulated proliferation was studied, and cytokine production in LPS-stimulated murine dendritic cells (DC). All four proteins inhibited LPS-induced splenocyte proliferation, though to different degrees, and independently of sialic acid. κ-Casein strongly inhibited PHA-induced proliferation and had a weak inhibitory effect on Con A-induced proliferation, whereas lactoferrin stimulated Con A-induced proliferation. κ-Casein, glycomacropeptide, and lactoferrin differentially affected cytokine production by DC: κ-casein significantly inhibited production of TNF-α, IL-10, -12, -6, and -1β, independent of sialic acid, whereas less-marked effects of glycomacropeptide and lactoferrin were seen. These findings thus point to important immunosuppressive effects of some milk proteins and indicate that they may function via different mechanisms.