Interleukin-10 (IL-10) is an anti-inflammatory cytokine with protective actions on the vasculature. On the other hand, endothelin (ET)-1 has potent vasoconstrictor, mitogenic, and proinflammatory activities, which have been implicated in the pathophysiology of a number of cardiovascular diseases. We hypothesized that, in a condition where ET-1 expression is upregulated, i.e., on infusion of TNF-α, IL-10 confers vascular protection from ET-1-induced injury. Aortic rings and first-order mesenteric arteries from male C57BL/6 (WT) and IL-10-knockout (IL-10−/−) mice were treated with human recombinant TNF-α (220 ng·kg−1·day−1) or vehicle (saline) for 14 days. TNF-α infusion significantly increased blood pressure in IL-10−/−, but not WT, mice. TNF-α augmented vascular ET-1 mRNA expression in arteries from WT and IL-10−/−mice. ET type A (ETA) receptor expression was increased in arteries from IL-10−/−mice, and TNF-α infusion did not change vascular ETAreceptor expression in control or IL-10−/−mice. Aorta and mesenteric arteries from TNF-α-infused IL-10−/−mice displayed increased contractile responses to ET-1, but not the ET type B receptor agonist IRL-1620. The ETAreceptor antagonist atrasentan completely abolished responses to ET-1 in aorta and mesenteric vessels, whereas the ERK1/2 inhibitor PD-98059 abrogated increased contractions to ET-1 in arteries from TNF-α-infused IL-10−/−mice. Infusion of TNF-α, as well as knockdown of IL-10 (IL-10−/−), induced an increase in total and phosphorylated ERK1/2. These data demonstrate that IL-10 counteracts ETA-mediated vascular responses to ET-1, as well as activation of the ERK1/2 pathway.