Arsenic exposure is associated with an increased risk of atherosclerosis and vascular diseases. While endothelial cells have long been considered to be the primary targets of arsenic toxicity, the underlying molecular mechanisms remain largely unknown. In this study, we sought to explore the signaling pathway triggered by sodium arsenite and its implication for endothelial phenotype. We found that sodium arsenite produced time- and dose-dependent decreases in human umbilical vein endothelial cell (HUVEC) viability. This effect correlated with the induction of p21^Cip1/Waf1 (up to 10-fold), a regulatory protein of cell cycle and apoptosis. We also found that arsenite-stimulated EGF (ErbB1) and ErbB2 receptor transactivation manifested as receptor tyrosine phosphorylation appeared to be a proximal signaling event leading to p21^Cip1/Waf1 induction, since both pharmacological inhibitors and knockdown of receptors by RNAi blocked arsenite-induced p21^Cip1/Waf1 upregulation. Arsenite-induced activation of JNK and p38 MAPK were distinct, with only JNK as a downstream target of the EGF receptor. Moreover, inhibition of JNK with SP600125 or dominant-negative MKK7 inhibited only p21^Cip1/Waf1 induction, whereas the p38 MAPK inhibitor SB203580 or dominant-negative MKK4 inhibited both p21^Cip1/Waf1 and p53 induction. Functionally, inhibition of p21^Cip1/Waf1 induction prevented endothelial apoptosis due to arsenite treatment. Insofar as endothelial dysfunction promotes vascular disease, these data provide a mechanism for the increased incidence of cardiovascular disease due to arsenite exposure.