The effects of various concentrations of Fe3+ (30-125 microM) and various doses of X-irradiation (10 to 30 Gy) on the survival of mouse peritoneal macrophages in culture was tested and compared with the effect of combinations of both Fe3+ and X-irradiation. Exposure of the cells to 30 microM Fe3+ or 10 Gy did not significantly alter the survival pattern, as compared with control cells. Greater dosages of iron or X-irradiation caused increasing cellular degeneration and death. When the combined effect of 30 microM Fe3+ and 10 Gy was tested a pronounced decrease in survival time was noted. The production of malondialdehyde (MDA) was studied in cells cultured with and without iron and after exposure to X-irradiation. The results indicated an increasing peroxidative capacity in parallel with increasing dose and extent of exposure to iron and irradiation. Combinations of 30 microM Fe3+ and 10 Gy resulted in enhanced MDA production as compared with these treatments alone (in which levels of MDA did not differ from those in controls). The findings support the theory that cells containing iron-loaded lysosomes are abnormally sensitive to X-irradiation due to the catalytic activity of the Fe2+ in equilibrium with Fe3+ redox system on lipid peroxidation. The postulated mechanism involves disruption of lysosomal membranes as a consequence of increased lipid peroxidation, resulting in leakage of potent lytic enzymes into the cell sap causing cellular degeneration and death.