Anthrax lethal toxin, which consists of two separate protein, protective antigen (83 KDa) and lethal factor (85 KDa) is responsible for major symptoms and death from systemic infection of Bacillus anthracis. High concentrations of this toxin are cytolytic to macrophages, whereas sublytic concentrations of lethal toxin induce these cells to produce interleukin $1{eta}$ ($IL-1{eta}$). It is proposed that melatonin and dehydroepiandrosterone (DHEA) may play an important role in modifying immune dysfunction. In this study, we investigated whether or not melatonin and DHEA could prevent $IL-1{eta}$ production that is induced by anthrax lethal toxin in mouse peritoneal macrophages. Treatment of melatonin or DHEA alone, as well as together, prevented the production of $IL-1{eta}$ caused by anthrax lethal toxin. We found that melatonin at a concentration of $10^{-6}-10^{-7}$ M inhibits $IL-1{eta}$ production induced by anthrax lethal toxin. As expect, treatment of DHEA at a concentration $10^{-6}-10^{-7}$ M also suppressed production of $IL-1{eta}$ by lethal toxin stimulated macrophages. The results of these studies suggest that melatonin and DHEA, immunomodulators, may have an important role in reducing the increase of cytokine production in anthrax lethal toxin-treated macrophages.