Inducible nitric oxide synthase (iNOS) has been shown to play an important role in the development of liver injury. iNOS deficiency protects mice from hemorrhage/resuscitation as well as from cytokine-mediated liver injury, for example, after administration of concanavalin A (con A). Here we investigated the in vivo effects of tumor necrosis factor (TNF)-α and/or interferon (IFN)-γ, two mediators of con A–induced liver injury, the TNF receptor (TNFR) usage leading to iNOS expression, and its connection with nuclear factor κB (NF-κB) activation. In conclusion, iNOS expression in vivo is dependent on both TNF-α and IFN-γ. Although con A–induced liver injury depends on both TNFR1 and TNFR2, TNF-dependent iNOS expression is mediated exclusively by TNFR1 and requires NF-κB activation.