Vascular cell adhesion molecule-1 (VCAM-1) is a mononuclear leukocyte-selective adhesion molecule that is expressed in human vascular endothelial cells at sites of local inflammation. It participates in local endothelial–monocyte interactions during the initiation of atherosclerosis. In the present study, endothelin alone did not induce the surface expression and mRNA accumulation of VCAM-1 in human vascular endothelial cells, but inhibition of endogenous nitric oxide (NO) by N^G-monomethyl-l-arginine enhanced the surface expression and mRNA accumulation of VCAM-1 stimulated by endothelin-1. It is conceivable that in human vascular endothelial cells, stimulation of an endothelin receptor results in the production of nitric oxide (NO), suppressing the expression of VCAM-1. Endothelin-1 enhanced the surface expression and mRNA accumulation of VCAM-1 in cells treated with tumor necrosis factor α (TNF-α). The enhancement by endothelin-1 may be explained by the inhibitory effect of TNF-α on endothelin-induced NO production. Pretreatment with BQ788 (an endothelin ET_B receptor antagonist) or inhibitors of nuclear factor kappa B (NF-κB) activation completely diminished the synergistic enhancement of VCAM-1 expression by endothelin-1 in TNF-α-stimulated vascular endothelial cells, both at the protein and mRNA levels. These findings suggest that the synergistic enhancement of VCAM-1 expression by TNF-α and endothelin ET_B receptor stimulation may be augmented by the induction of NF-κB binding activity in human vascular endothelial cells.