Lipopolysaccharide (LPS) induces rapid necrosis of intradermal fibrosarcomas in mice. The mechanism(s) by which LPS produces tumor necrosis has been investigated using histocompatible LPS-sensitive (C3H/HeN) and LPS-resistant (C3H/HeJ) mouse strains. C3H/HeN- or C3H/HeJ-derived fibrosarcomas were necrotized by LPS when they were grafted onto C3H/HeN mice but were not affected when growing on C3H/HeJ mice, indicating that LPS does not act directly on the tumor itself. In contrast, lethally X-irradiated C3H/HeJ mice exhibit necrosis of their tumors when reconstituted with C3H/HeN bone marrow cells, whereas C3H/HeN mice no longer exert LPS-induced tumor necrosis after the adoptive transfer of C3H/HeJ bone marrow cells. These findings clearly indicate that LPS produces necrosis of tumors by activating host lymphoreticular cells.