We have shown that mitochondrial DNA-depleted (ρ0) SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of ρ0 cells. We studied the changes of gene expression in SK-Hep1 ρ0 cells. DNA chip analysis showed that MnSOD expression was profoundly increased in ρ0 cells. O2.- contents increased during ρ0 cell derivation but became normalized after establishment of ρ0 phenotypes, suggesting that MnSOD induction is an adaptive process to increased 02.-. ρ0 cells were resistant to menadione, paraquat, or doxorubicin, and O2 .- contents after treatment with them were lower in ρ 0 cells compared with parental cells because of MnSOD overexpression. Expression levels and activity of glutathione peroxidases were also increased in ρ0 cells, rendering them resistant to exogenous H 2O2. ρ0 cells were resistant to p53, and intracellular ROS contents after p53 expression were lower compared with parental cells. Other types of ρ0 cells also showed increased A1n801) expression and resistance against ROS. Heme oxygenase-1 expression was increased in ρ0 cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in ρ0 cells and their resistance against ROS donors. These results indicate that ρ0 cells are resistant to cell death contrary to previous reports and suggest that an adaptive increase in the expression of antioxidant enzymes renders cancer cells or aged cells with frequent mitochondrial DNA mutations to resist against oxidative stress, host anti-cancer surveillance, or chemotherapeutic agents, conferring survival advantage on them.