In summary, AMD was rendered hepatotoxic in rats in the presence of a coexisting inflammatory stress induced by LPS. AMD/LPS-cotreated rats developed liver pathology and blood chemistry changes that resemble AMD-induced idiosyncratic hepatotoxicity in human patients. LPS did not interact with AMD by changing the metabolism or distribution of AMD. AMD enhanced the increase in plasma TNF concentration caused by LPS, and neutralizing TNF reduced liver injury from AMD/LPS coexposure. Moreover, TNF potentiated the cytotoxicity of both AMD and DEA in vitro. These findings add support to the idea that inflammatory stress can interact with IADR-associated drugs to cause liver injury by a mechanism involving TNF and suggest that a similar mode of action might apply to several drugs that cause idiosyncratic hepatotoxicity in humans.