EL4 murine lymphoma cells and F9 murine teratocarcinoma cells undergo apoptosis-like cell death after exposure to ionizing radiation. Apoptosis differs in several ways from classical clonogenic cell killing by radiation. We have tested several modifiers and radiomimetic agents in an effort to determine if the mechanism of induction of apoptosis by radiation differs from the mechanism of classical clonogenic cell killing by radiation, and consequently that these two end points of radiation action might be differentially modifiable. We found that internucleosomal DNA fragmentation, characteristics of apoptosis, can result from treatment of EL4 and F9 cells with agents that have diverse modes of action: tert-butyl hydroperoxide, diazenedicarboxylic acid bis(N,N-piperidide), and etoposide. Hydrogen peroxide did not induce internucleosomal DNA fragmentation at concentrations expected to be produced by the doses of ionizing radiation that we used. Radiation-induced DNA fragmentation could be inhibited by 3-aminobenzamide, dibutryl cyclic AMP, or 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, although in this respect there appear to be marked differences between the cell lines.