Histamine is an important agent of innate immunity, transiently increasing the flux of immune competent molecules from the vascular space to the tissues, and then allowing rapid restoration of the integrity of the endothelial barrier. (25) In previous work we found that histamine alters the endothelial barrier by disrupting cell-cell adhesion and identified VE-cadherin as an essential participant in this process. (16, 24) The previous work did not determine if histamine directly interrupted VE-cadherin adhesion, if the effects of histamine were selective for cadherin adhesion, or if capacitive calcium flux across the cell membrane was necessary for the effects of histamine on cell-cell adhesion. In the current work we found that histamine directly interrupts adhesion of L-cells expressing the type 1 histamine (H1) receptor and VE-cadherin to a VE-cadherin-Fc fusion protein. In contrast, integrin mediated adhesion to fibronectin of the same L-cells expressing the H1 receptor was not affected by histamine, demonstrating that the effects of histamine are selective for cadherin adhesion. Some of the effects of many edemagenic agonists on endothelium are dependent on the capacitive flux of calcium across the endothelial cell membrane. Blocking capacitive calcium flux with LaCl3 did not prevent histamine from interrupting VE-cadherin adhesion of transfected L-cells, nor did it prevent histamine from interrupting cell-cell adhesion of human umbilical vein endothelial cells. These data support the contention that histamine directly and selectively interrupts cadherin adhesion, and this effect on cadherin adhesion is independent of capacitive calcium flux.