Naringin (NG), a flavonoid in grapefruit and citrus, has been reported to exhibit antioxidant effects and pharmacological actions. Recently, we have reported that NG suppressed the cytotoxicity and apoptosis induced by H(2)O(2), a typical pro-oxidant, in mouse leukemia P388 cells. Cytosine arabinoside (1-beta-d-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite chemotherapeutic drug used for acute leukemia. It has been suggested that Ara-C-induced cytotoxicity is caused by apoptosis, which is mediated by reactive oxygen species (ROS). In this study, we examined the effect of NG on the cytotoxicity and apoptosis in mouse leukemia P388 cells treated with Ara-C. Ara-C caused cytotoxicity in a concentration and time-dependent manner in the cells. N-Acetyl-L-cysteine (NAC), cystamine (CysA) or a reduced form of glutathione (GSH), typical antioxidants significantly blocked Ara-C-induced cytotoxicity. Similarly, Ara-C-induced cell death was completely prevented by NG. NG strongly reduced ROS production caused by Ara-C in the cells. NG slightly increased the activities of antioxidant enzymes, catalase and glutathione peroxidase. Ara-C caused apoptosis with nuclear morphological change and DNA fragmentation. NG remarkably attenuated the Ara-C-induced apoptosis. NG completely blocked the DNA damage caused by Ara-C treatment at 6 h using the Comet assay. Our data suggest that NG reduces Ara-C-induced oxidative stress through both an inhibition of the generation of ROS production and an increase in antioxidant enzyme activities. Consequently, NG blocked apoptosis caused by Ara-C-induced oxidative stress, resulting in the inhibition of the cytotoxicity of Ara-C.