Decreased oxygen tension is one important component of ischemic episodes, which are characterized by leukocyte accumulation at the site of infarction. We have reported recently that cultured endothelial and muscle RD cells transferred from pO2 of 120 torr to pO2 of 50 torr for 3 h dramatically increased their adhesiveness for lymphocytes and neutrophils. In the present study, we identify and characterize a new endothelial cell adhesion molecule that mediates hypoxia-induced adhesion to leukocytes. We have generated a mAb, HAL 1/13, that recognizes a cell surface epitope common to both RD and endothelial cells and inhibits lymphocyte and neutrophil adhesion to muscle and endothelial cell monolayers under normoxic conditions in a dose-dependent manner. The contribution of the HAL 1/13 ligand to leukocyte adhesion significantly increased (more than twofold) when the muscle or endothelial cells had been exposed previously to a hypoxic environment. HAL 1/13 mAb completely abolished the enhancing effect of hypoxia on RD and endothelial cell adhesiveness for leukocytes. HAL 1/13 mAb immunoprecipitated a protein with Mr approximately 85,000 Da from cell surface-iodinated muscle and endothelial cells. The Mr, CD cluster dendrogram analysis, and lack of induction by IL-1 of HAL 1/13 distinguish it from most other known endothelial cell adhesion molecules. We suggest that this hypoxia-sensitive adhesion receptor on mesenchymal cells participates in neutrophil adhesion and consequent diapedesis during hypoxia-associated pathologic conditions.