Upregulation of the glial fibrillary acidic protein (GFAP) in astrocytes is a hallmark of the phenomenon known as reactive gliosis and, yet, the function of GFAP in this process is largely unknown. Our previous studies have shown that mature astrocytes react vigorously to substrate bound beta-amyloid protein (BAP) in a variety of ways (i.e., increased GFAP, enhanced motility, unusual aggregation patterns, inhibitory ECM production). In order to uncover which, if any, of these phenomena are causally related to the function of GFAP, primary cortical astrocytes from transgenic mice lacking GFAP were cultured on BAP substrates at low or high density and at various lengths of time following in vitro maturation. Differences between mutant and control cells became progressively more obvious when cells were matured in vitro for two weeks or longer and especially in cultures that were at high density. Mature control astrocytes show a dramatic response to BAP by aggregating into a meshwork of rope-like structures that completely bridge over the peptide surface. In marked contrast, mature GFAP-null astrocytes initiate the response much more slowly and had a much reduced ability to aggregate tightly. Furthermore, we prepared hippocampal slice cultures from GFAP-/- and GFAP+/+ mice and compared their astrocytic responses to injected BAP. GFAP-/- astrocytes of hippocampal slice cultures failed to form a barrier-like structure around the edge of the BAP deposit as did GFAP+/+ astrocytes. Our data suggest that GFAP may be essential for mature astrocytes to constrain certain types of highly inflammatory lesions in the brain.