Oxygen centered radicals derived from potassium superoxide (KO2) in solution were found to be toxic to P815 mastocytoma target cells. Protection of P815 cells from chemically generated radicals was mediated most efficiently by Tiron, a low molecular weight scavenger of superoxide radicals (O2-). Superoxide dismutase (SOD) and catalase also afforded protection. In vivo cytolysis of P815 target cells mediated by allogeneic lymphocytes sensitized in vivo to tumor cells was inhibited by reducing the amount of oxygen available for metabolism and by radical scavengers. Ferricytochrome c, Tiron, and phenol, all of which are relatively low molecular weight radical scavengers, inhibited cytolysis in a dose-dependent manner, while mannitol, a hydroxyl radical scavenger, did not. High molecular weight scavengers like SOD and catalase had no effect. The inhibition of cytolysis by radical scavengers was found to be independent of toxic effects on effector cells, chelation of ions, or indirect effects on prostaglandin biosynthesis. Pretreatment of either effector or target cells with Tiron had no effect on LMC. The data suggest a possible role for free radicals in molecular events leading to target cell injury by sensitized lymphocytes.