Interleukin-1 (IL-1) and tumor necrosis factor (TNF) selectively induce mitochondrial manganese superoxide dismutase (MnSOD) production in various cell types. We have evaluated the capacity of tumor cells that overexpress MnSOD to recover from the cytostatic and cytotoxic effects of cytokines (IL-1 and TNF), chemotherapeutic agents, and ionizing irradiation. Clones of human melanoma cell line, A375, which overexpressed MnSOD after sense MnSOD cDNA transfection, showed increased recovery from treatment with cytostatic and cytotoxic doses of IL-1 alpha and TNF alpha, whereas clones of A375 cells that were transfected with anti-sense MnSOD cDNA recovered less well than normal cells from IL-1 alpha and TNF alpha. In addition, Chinese hamster ovary (CHO) cells transfected with sense MnSOD cDNA showed increased survival after treatment with doxorubicin, mitomycin C, and gamma (gamma) radiation in vitro. It is hypothesized that mitochondrial MnSOD, by scavenging oxygen radicals induced by cytokines, some cytotoxic drugs, and ionizing radiation, is protective and promotes the survival of cells from the lethal effects of these treatments.