Acute respiratory distress syndrome (ARDS) is a serious, often fatal condition without available pharmacotherapy. While the role of innate cells in ARDS has been studied extensively, emerging evidence suggests that T cells may be involved in disease etiology. Staphylococcus aureus enterotoxins are potent T cell mitogens capable of triggering life-threatening shock. We demonstrate that 2 days after inhalation of S. aureus enterotoxin A, mice developed T cell-mediated increases in vascular permeability, as well as expression of injury markers and caspases in the lung. Pulmonary endothelial cells underwent sequential phenotypic changes marked by rapid activation coinciding with inflammatory events secondary to T cell priming, followed by reductions in endothelial cell number juxtaposing simultaneous T cell expansion and cytotoxic differentiation. Although initial T cell activation influenced the extent of lung injury, CD54 (ICAM-1) blocking antibody administered well beyond enterotoxin exposure substantially attenuated pulmonary barrier damage. Thus, CD54-targeted therapy may be a promising candidate for further exploration into its potential utility in treating ARDS patients.