Although considerable work has focused on understanding the direct cellular injury caused by sulfur mustard (SM) exposure, less is known of the mechanisms controlling the SM induced inflammatory responses. Animal and human studies have shown that SM lesions contain a number of pro-inflammatory cytokines that are known chemoattractants for inflammatory cells such as polymorphonuclear leukocytes (PMN). PMN constitute the first line of defense in host innate immune responses to injury and infection and produce reactive oxygen species (ROS) as well as a number of proteolytic enzymes as part of their anti-microbial function. The anti-microbial agents expressed by PMN can also cause collateral damage in the tissues where they are released, destroying cells and breaking down components of the extracellular matrix (ECM). The ability to cause bystander tissue injury and the potential to modulate the inflammatory environment make PMN a likely player in SM histopathology. We have conducted preliminary experiments to address how PMN might influence the progression of SM injury by comparing the histopathology, resulting from SM exposure, of normal mice to those depleted of PMN. Mice were depleted of PMN by injection with an anti-PMN monoclonal antibody (mAb) prior to being exposed to 160 μg SM (in absolute ethanol) on the inner surface of the left ear. At 24 hours post-exposure, there is pyknosis of the epidermal keratinocytes in both the ears of the normal and depleted mice with some necrotic condensation of the epidermis. At 48 hours post-exposure, there is a significant PMN infiltrate in theexposed ears of the undepleted mice with marked necrosis of the epidermal layer, indicated by the loss of organization of nucleated cells. This is in contrast to the exposed ear in the PMN depleted mice that, though necrotic, still shows distinct nucleated cellularity in the epidermal layer. At a higher dose of SM, 250 μg/ear, normal mice undergo coagulative injury within 48-60 hours. The coagulative injury manifests as a loss of detectable circulation in the exposed extremity caused by platelet aggregation, thromboses in the microvasculature and withering of the ear. At 24 hours post-exposure, no difference was detected between the normal and PMN depleted mice, with both groups showing equivalent edema and serum protein extravasation in the exposed ear. At 48 hours, however, 63% of normal mice showed coagulative tissue damage in the exposed ear compared to only 25% of the PMN depleted mice showing damage. Taken together these data indicate that the rate of epithelial necrosis and the expression of coagulative factors resulting from epithelial exposure to SM can be affected by the presence of PMN.