Anthrax toxin is made up of three separate protein components: the receptor-binding protective antigen (PA), the adenylyl cyclase edema factor (EF), and the metalloproteinase lethal factor (LF). EF and PA constitute edema toxin (ET), which causes edema when injected subcutaneously. At higher doses, ET causes severe pathologies and death in BALB/cJ mice (A. M. Firoved et al., Am. J. Pathol. 167:1309-1320, 2005). A striking effect of ET at lethal doses is adrenal necrosis. Here we show that low doses of ET (10 microg) that produce no overt signs of illness in mice still cause substantial adrenal lesions. These lesions are not associated with reduced corticosterone production; instead, ET-treated mice have increased corticosterone production. Because the resistance of mice to the other component of anthrax toxin, lethal toxin (LT; LF plus PA), has been shown to be overcome by the perturbation of the endocrine system, we hypothesized that sublethal doses of ET might sensitize LT-resistant DBA/2J mice to LT-mediated lethality. We report that a low dose of ET (5 microg) is sufficient to sensitize DBA/2J mice when given concurrently with LT. Higher doses of ET (e.g., 15 microg) given to male and female DBA/2J mice 18 h prior to LT challenge also sensitize them to LT. This study using highly purified ET and LT demonstrates how the components of anthrax toxin can work together to increase lethality.