Invariant Natural Killer T (iNKT) cells are involved in the intrahepatic immune response and in hepatitis. In particular, iNKT lymphocytes are responsible for hepatocyte death in concanavalin A-induced hepatitis in mice. We examined the role of iNKT cells in acute hepatitis induced by a hepatotoxic agent, carbon tetrachloride (CCl(4) ). WT and iNKT cell-deficient (Jα18(-/-) ) mice were challenged with a single dose of 2.4 g/kg CCl(4) and both hepatic physiopathology and immune responses were studied. Plasma alanine and aspartate amino-transferase levels were significantly higher in Jα18(-/-) mice than WT mice two days after CCl(4) administration (15000 versus 7000 UI/L AST). We tested various inflammatory markers: CXCL1/KC and MMP-8, respectively, a chemoattractant for and protease produced by neutrophils, were significantly higher in iNKT cell-deficient than control mice. The more severe injury of the liver in Jα18(-/-) mice was associated with more leukocyte infiltrate, enriched in neutrophils (CD11b(+) CD11c(-) Gr-1(+) cells) in agreement with CXCL1/KC and MMP-8 levels. Complementary experiments with NK-depleted animals indicate a minor role for NK cells in the greater damage to the liver of iNKT-deficient mice. Thus, unlike for ConA-induced hepatitis, we report that iNKT cells protect the liver against acute hepatitis induced by CCl(4) and limit neutrophil infiltration.