Concanavalin A induces NKT cell-mediated liver damage. Glucocerebroside (GC) is a naturally occurring glycolipid. Aims: To determine the effect of GC in a murine model of ConA-induced hepatitis. Methods: Group A and B mice were treated with GC 2 hours prior to and 2 hours following administration of Con A, respectively; group C mice were treated with Con A; group D mice were treated with GC; group E mice did not receive any treatment. Liver damage was evaluated by serum AST and ALT levels and liver histology. The immune effect of GC was determined by FACS analysis of intrahepatic and intrasplenic NKT lymphocytes, measurement of cytokine levels, and western blot analysis for STAT 1, 4, 6 and NFB expression. The effect of GC on NKT cell proliferation was assessed in vitro. Results: Serum AST and ALT levels were markedly reduced in GC-treated group A mice compared to non-treated group C animals, and histological damage was markedly attenuated in group A. The beneficial effect of GC was associated with a 20% decrease of intrahepatic NKT lymphocytes, significant lowering of serum IFN levels and decreased STAT1 and STAT6 expression. In vitro, administration of GC led to a 42% decrease of NKT cell proliferation in the presence of dendritic cells, but not in their absence. IP administered radioactive GC was detected in the liver and bowel. Conclusions: Administration of GC led to amelioration of Con A hepatitis, associated with an inhibitory effect on NKT lymphocytes. GC holds promise as a new immune-modulatory agent.