Soluble intercellular adhesion molecule-1 (sICAM-1) is elevated in the cerebrospinal fluid of patients with severe brain trauma and mouse sICAM-1 induces the production of macrophage inflammatory protein-2 (MIP-2) in mouse astrocytes. The production of MIP-2 is greatly enhanced when sICAM-1 contains sialylated complex-type N-glycans (sICAM-1-CT) as produced by Chinese hamster ovary (CHO) cells. By contrast, sICAM-1 from the Lec1 mutant of CHO cells (sICAM-1-HM), containing only high mannose-type N-glycans, is relatively inactive. Here we show that the Nglycans of sICAM-1-CT are mostly 2,3-sialylated bi-, tri-, and tetraantennary complex-type structures with varying amounts of core fucosylation. Unexpectedly, sICAM-1-CT and sICAM-1-HM bound equivalently to mouse astrocytes. Enhanced MIP-2 induction by sICAM-1-CT was associated with a more rapid, higher level, and prolonged MIP-2 response as well as sICAM-1-CT accumulation at the plasma membranes of mouse astrocytes. These results show that glycosylation of sICAM-1 contributes to its signaling properties at the astrocyte cell surface, and suggest that altered glycosylation which might arise as a result of inflammation could regulate the bioactivity of sICAM-1.