Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. C-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 hours post-injury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 hours post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild type mice; further, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. BrdU incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 hours in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression were increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.