Using immunological techniques, we have shown for the first time that change in the nuclear matrix is an observable step in the cell death program. Immunometric assays detect soluble nuclear matrix proteins in the culture supernatants of cells killed by adriamycin, tumor necrosis factor and serum growth factor deprivation. Studies of cells killed by tumor necrosis factor and serum growth factor deprivation using dual immunofluorescent and 4'-6-diamidino-2-phenylindole (DAPI) staining detect many cells strongly positive for DNA that have little or no nuclear matrix protein. The staining pattern of cells killed by adriamycin is very different. There is good correspondence between the immunofluorescent and DAPI staining patterns indicating the presence of nuclear matrix proteins and DNA, although at a reduced ratio. It is concluded that the nuclear matrix changes are dependent on the agents that trigger cell death.