Curcumin (CUR; diferuloylmethane), a rhizome extract of Curcuma Longa L. is commonly used as a food coloring and flavoring agent. Although oriental and Ayurvedic medicines have traditionally used CUR in the treatment of diseases, conventional medicine has just begun to recognize its potential therapeutic value. Numerous recent studies have demonstrated the ability of CUR to halt or prevent certain types of cancer, decrease inflammation, and improve cardiovascular health. However, very few studies have examined its ability to protect against drug-induced organ injury. This study explored whether CUR pre-exposure has the potential to prevent acetaminophen (APAP)-induced: (i) hepatotoxicity, (ii) genomic injury, (iii) oxidative stress in the liver, and (iv) apoptotic and necrotic cell deaths in the liver in vivo. Additional goals were to investigate the interplay of pro- and anti-apoptotic genes and their ultimate impact on various forms of cell death. In order to study the CUR-APAP interaction, male B6C3F1 mice were gavaged with CUR (17 mg/kg/day, p.o.) for 12 days followed by a single APAP exposure (400 mg/kg, ip). Four groups of animals (control, CUR, APAP, CUR+APAP) were sacrificed 24 h after APAP exposure. The results indicated that APAP-induced liver injury associated events as serum ALT (80-fold), lipid peroxidation (357%) and DNA fragmentation (469%) were markedly reduced to 3-fold, 134% and 162%, respectively, in the CUR+APAP group. The APAP-induced increase in expression of pro-apoptotic genes (Bax, caspase-3) decreased while expression of anti-apoptotic genes (Bcl-XL) increased in CUR preexposed mouse livers, and these changes were mirrored in the pattern of apoptotic and necrotic cell deaths. Levels of DNA damage sensor P⁵³ and its counterpart Mdm2 were also analyzed during this interaction. Based on the available literature, and these results, it seems likely that CUR may impart global protection in vivo against drug-induced liver injury by opposing several crucial events instrumental to both apoptosis and necrosis.