Endothelial cell death and replication was analyzed in the rat aorta with the use of combined IgG immunocytochemistry and 3H-thymidine autoradiography. Dead and replicating cells were clustered in the aortic endothelium of normal rats with a low level of spontaneous cell death and replication. Death and replication were also clustered in rats treated with endotoxin (Escherichia coli lipopolysaccharide [LPS]), a substance which is cytotoxic to endothelial cells in culture. LPS caused a dramatic increase both in endothelial cell death and replication, while no endothelial denudation could be discerned with the use of the 111In-labeled platelet technique. We conclude that endothelial cell death and replication are topographically clustered phenomena, which may imply that cell death leads to a local stimulation of cell replication. Furthermore, LPS induces a massive cell death, which is paralleled by cell replication, yet does not cause any significant increase in denudation. This suggests that the primary effect of LPS on the vessel wall is its cytotoxicity for endothelial cells. Endothelial cell death appears to provide the stimulus for cell replication both in normal and in LPS-treated rats.