BACKGROUND & AIMS: : Bacillus Calmette-Guerin (BCG) infection causes hepatic injury following granuloma formation and secretion of cytokines which renders mice highly sensitive to endotoxin-mediated hepatotoxicity. Tumor necrosis factor (TNF) is required for granuloma formation and is one of the most important cytokines in liver injury. TNF inhibitors are effective therapies for inflammatory diseases. However, clinical use of non-selective TNF inhibitors is associated with an increased risk of infections. This work investigates the differential roles of soluble TNF (solTNF) and membrane TNF (memTNF) in BCG infection, BCG/LPS- and D-GALN/LPS-induced liver injury. METHODS: We have used both genetic and pharmacologic approaches and analyzed liver injury, TLR4, cytokine and iNOS activation induced by BCG, BCG/LPS and D-GALN/LPS. RESULTS: BCG infection-induced liver injury is seen in wild-type mice but not in TNF(-/-), memTNF knock-in (KI), and sTNFR1-Fc transgenic mice. Severity of BCG-induced liver injury is correlated with BCG-granuloma number and hepatic expression of TLR4 and iNOS. In addition, protection from liver damage caused by BCG/LPS or D-GALN/LPS administration was observed in TNF(-/-), memTNF KI and sTNFR1-Fc transgenic mice. To extend the genetic findings, we then evaluated whether selective pharmacological inhibition of solTNF by dominant-negative (DN)-TNF neutralization and non-selective inhibition of solTNF and memTNF by anti-TNF antibodies and etanercept (TNFR2-IgG1) can protect the mice from liver injury. Both selective and non-selective inhibition of solTNF protected mice from BCG/LPS and D-GALN/LPS-induced liver damage. CONCLUSIONS: These data suggest that memTNF is not mediating liver injury and that selective inhibition of solTNF sparing memTNF may represent a new therapeutic strategy to treat immune-mediated inflammatory liver diseases.