The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeruginosa exotoxin A (PEA). In both models, leptin-deficient (ob/ob) mice were protected from liver damage and showed lower induction of tumor necrosis factor (TNF) α and IL-18 compared with their lean littermates. Neutralization of TNF-α reduced induction of IL-18 by either Con A (70% reduction) or PEA (40% reduction). Pretreatment of lean mice with either soluble TNF receptors or with an anti-IL-18 antiserum significantly reduced Con A- and PEA-induced liver damage. The simultaneous neutralization of TNF-α and IL-18 fully protected the mice against liver toxicity. However, neutralization of either IL-18 or TNF-α did not inhibit Con A-induced production of IFN-γ. Thymus atrophy and alterations in the number of circulating lymphocytes and monocytes were observed in ob/ob mice. Exogenous leptin replacement restored the responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency leads to reduced production of TNF-α and IL-18 associated with reduced T cell-mediated hepatotoxicity. In addition, both TNF-α and IL-18 appear to be essential mediators of T cell-mediated liver injury.