We studied the role of the natural triterpenoid miliacin (3-3-methoxy-Al8-oleanene) in the regulation of oxidative stress in the liver of (CBAxC57B1(6))F1 mice exposed to methotrexate. Miliacin attenuated methotrexate-induced lipid peroxidation as determined by an attenuation of thiobarbituric acid-reacting products in the liver. Furthermore, miliacin normalized the expression of genes encoding the 2e1 isoform of cytochrome P-450 and glutathione reductase that were dramatically dysregulated by methotrexate. These results established the role of miliacin in modulation of redox genes, thereby providing evidence for a new mechanism of organ protection by this triterpenoid.