Acetaminophen is directly cytotoxic to hepatocytes through its conversion to the reactive intermediate NAPQI (1). In this issue of the JCI, Imaeda and colleagues provide evidence that DNA released from acetaminophen-damaged hepatocytes induces an innate immune response in the liver that augments the injury caused by the drug alone (18). They show in a mouse model that acetaminophen, which damages hepatocytes, as well as damaged DNA per se, activates Tlr9 within SECs, thereby stimulating the production of pro–IL-1β and pro–IL-18. Acetaminophen treatment also promotes activation of the Nalp3 inflammasome in SECs, whose function is to activate caspase-1 and promote the cleavage of pro–IL-1β and pro–IL-18 to their mature, active forms (6). (The specific stimulus to Nalp3 activation in the acetaminophen-treated liver is unknown, but potential candidates include uric acid, ATP, and DNA.) IL-1β and IL-18 in turn enhance acetaminophen-induced liver injury by promoting hepatic inflammation and secondary tissue damage. Imaeda et al. further demonstrate that this immune-mediated amplification of acetaminophen-induced liver injury can be blocked by aspirin. Aspirin prevents hepatic induction of pro–IL-1β and pro–IL-18 and may have an independent inhibitory effect on the Nalp3 inflammasome.