Sappanchalcone, a biologically active compound isolated from Caesalpinia sappan L., is reported to exert a variety of biological activities, such as neuroprotective, anti-inflammatory actions and inhibitory effect on antigen-induced beta hexosaminidase release. However, the vascular protective effects of this compound are not fully understood. The present study examined the effects of sappanchalcone in suppressing cell adhesion molecules expression in high glucose stimulated human umbilical vein endothelial cells (HUVEC). Sappanchalcone significantly decreased 25 mM high glucose-induced vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) expression in a dose-dependent manner. Sappanchalcone also significantly inhibited the formation of intracellular reactive oxygen species (ROS). Furthermore, we found that the vascular protective effects of sappanchalcone were linked to the up-regulation of heme oxygenase-1 expression in HUVEC. The effects of sappanchalcone on the high glucose-induced expression of VCAM-1 and ICAM-1 were partially reversed by treatment of the cells with an inhibitor of HO-1, tin protoporphyrin IX (SnPP). Based on these results, these findings suggest that sappanchalcone-induced HO-1 expression plays a key role in the vascular protective effects of sappanchalcone in HUVEC.