Expression of cell adhesion molecule (CAM) in endothelial cells upon activation by human immunodeficiency virus (HIV) infection is associated with the development of atherosclerotic vasculopathy. We postulated that induction of vascular cell adhesion molecule-1 (VCAM-1) by HIV-1 tat protein in endothelial cells might represent an early event that could culminate in inflammatory cell recruitment and vascular injury. We determined the role of HIV-1 tat protein in VCAM-1 expression in human pulmonary artery endothelial cells (HPAECs). HIV-1 tat protein treatment significantly increased cell-surface expression of VCAM-1 in HPAECs. Consistently, mRNA expression of VCAM-1 was also increased by HIV-1 tat protein as measured by RT-PCR. HIV-1 tat protein-induced VCAM-1 expression was abolished by the NF-B inhibitor pyrrolidine dithiocarbamate (PDTC) and the p38 MAPK inhibitor SB203580. Furthermore, HIV-1 tat protein enhanced DNA binding activity of NF-B, facilitated nuclear translocation of NF-B subunit p65, and increased production of reactive oxygen species (ROS). Similarly to VCAM-1 expression, HIV-1 tat protein-induced NF-B activation and ROS generation were abrogated by PDTC and SB203580. These data indicate that HIV-1 tat protein is able to induce VCAM-1 expression in HPAECs, which may represent a pivotal early molecular event in HIV-induced vascular/pulmonary injury. These data also suggest that molecular mechanism underlying the HIV-1 tat protein-induced VCAM-1 expression may involve ROS generation, p38 MAPK activation and NF-B translocation, which are the characteristics of pulmonary endothelial cell activation.