The present study was designed to investigate the role of IFN-γ in LPS-induced liver injury following priming with Propionibacterium acnes. At 1 week after priming BALB/c mice with P. acnes, a large number of macrophages (Mφ) and lymphocytes predominantly infiltrated the portal area, resulting in the intrahepatic formation of granulomas consisting of epithelioid and lymphoid cells. In comparison, in IFN-γ gene-disrupted BALB/c mice (IFN-γ knockout mice), the number of infiltrated Mφ was decreased, with a significant reduction in the number and size of granulomas. Subsequent elicitation with a low dose of LPS induced massive hepatic necrosis in wild-type BALB/c mice, with a marked increase in the serum levels of TNF-α, IL-12, and IL-18 and subsequently of alanine transferase. In contrast, IFN-γ knockout mice developed scattered focal necrosis of the liver with significantly lower levels of serum alanine transferase as well as drastic decreases in TNF-α, IL-12, and IL-18 production. The administration of an anti-IFN-γ neutralizing mAb at the eliciting phase significantly alleviated liver injury and reduced serum IL-12 and IL-18 levels. Thus, endogenously produced IFN-γ is involved in the pathogenesis of this liver injury model by regulating Mφ infiltration and granuloma formation in the priming phase as well as cytokine production in the eliciting phase.