Acute liver injury is a common cause of intensive care unit visits. In these studies, we used a murine model of acetaminophen poisoning to examine the role of stem cell factor (SCF) on liver damage. In the initial studies, we identified that the liver produces relatively high constitutive levels of SCF. Upon administration of acetaminophen, the levels of SCF fell dramatically, correlating to damage within the liver. When the liver was allowed to regenerate, the levels of SCF again correlated with the liver regeneration. We next treated mice with anti-SCF before sublethal doses of acetaminophen and significantly increased lethality in anti-SCF–treated animals. When exogenous SCF was given to mice, the lethality was significantly reduced compared with the control acetaminophen-treated animals and the damage within the liver tissue was attenuated. The administration of rSCF reduced the level of steady-state mRNA for cytochrome P450 cyp2E1 enzyme both in vitro and in vivo. These data suggest that SCF functions as an important factor that protects livers from acute damage.