Vascular necrosis and neovascularization are known consequences of sulfur mustard (HD)-induced tissue damage and are consistent with vascular remodeling. The effect of HD exposure on the overall integrity of the vascular system is unclear. Because HD is a potent alkylating agent and associated with protease degradation, we hypothesized that HD causes changes in vascular smooth muscle cell (VSMC) protein expression associated with vascular remodeling and differentiation. Fluorescent staining of the cytoskeleton demonstrates a dose dependent (25-400 μM) disruption of actin filaments indicating a generally compromised vascular integrity occurring 24 hrs after HD exposure. We also measured the effects of HD on expression of the functionally important proteins and general protein profiles in human VSMC. Two-dimensional (2D) gel electrophoresis performed on primary VSMC and endothelial cells indicates profound changes in vascular protein expression after HD exposure. Western blot analysis reveals a decrease in specific contractile protein expression that is concentration and time post HD exposure dependent. Expression of smooth muscle actin is decreased 24 hrs after 400 μM HD exposure. Four hours after high HD exposure VSMC exhibited no smooth muscle myosin expression, which returned to control levels after 24 hrs. These data suggest that HD can have a profound effect on VSMC tissue that involves dynamic changes in structural and functional protein expression. These data will help elucidate pathophysiological mechanisms within the vasculature that may be of critical importance in developing accurate and effective countermeasures to HD exposure.