Cerebral amyloid angiopathy (CAA) is a major pathological feature of Alzheimer's disease and related disorders. Human cerebrovascular smooth muscle (HCSM) cells, which are intimately associated with CAA, have been used as an in vitro model system to investigate pathologic interactions with amyloid β protein (Aβ). Previously we have shown that pathogenic forms of Aβ induce several pathologic responses in HCSM cells including fibril assembly at the cell surface, increase in the levels of Aβ precursor, and apoptotic cell death. Here we show that pathogenic Aβ stimulates the expression and activation of matrix metalloproteinase-2 (MMP-2). Furthermore, we demonstrate that the increase in MMP-2 activation is largely caused by increased expression of membrane type-1 (MT1)-MMP expression, the primary MMP-2 activator. Finally, treatment with MMP-2 inhibitors resulted in increased HCSM cell viability in the presence of pathogenic Aβ. Our findings suggest that increased expression and activation of MMP-2 may contribute to HCSM cell death in response to pathogenic Aβ. In addition, these activities may also contribute to loss of vessel wall integrity in CAA resulting in hemorrhagic stroke. Therefore, further understanding into the role of MMPs in HCSM cell degeneration may facilitate designing therapeutic strategies to treat CAA found in AD and related disorders.