Endotoxin (LPS) exposed to 100–200 kGy of γ radiation no longer induced rabbit platelet aggregation in vitro and it had a reduced ability to cause mitogenesis of B-lymphocytes from C57BL/6 mice. When tested in B6CBF1 mice exposed to 10 Gy60Co radiation 3 or 7 days previously, 300 μg of unirradiated LPS, which caused no mortality in unirradiated mice, killed 60 and 44% of the mice when given on days 3 or 7 post-radiation, respectively. Similarly, 60% of C57BL/6 mice engrafted with 5 × 106Lewis lung carcinoma cells 3 days before challenge with 300 μg of normal LPS died, but no animals given irradiated LPS died.One hundred micrograms of either LPS preparation caused 80 to 100% mortality of NMRI mice when given simultaneously with 105liveK. pneumoniae. No deaths were obtained if 50 μg of irradiated LPS were administered with 105bacteria, but 50 μg of unirradiated LPS caused 100% mortality. Similar mortalities were obtained when 100 μg of either toxin preparation were given 24 hr postinfection, but these were lower than those obtained with the simultaneous challenge. Endotoxin given 24 hr before 105organisms was less toxic than that given at the other times, and irradiated LPS caused fewer deaths than did unirradiated LPS. Similar results were seen when 106cells were used to challenge mice. Treatment 24 hr before challenge caused 70% mortality with unirradiated LPS compared to 30% mortality with irradiated LPS. All mice challenged with 107bacteria 24 hr after treatment with saline or unirradiated LPS died by 72 hr postinfection, but only 50% mortality was obtained in mice given irradiated LPS. Furthermore, none of these mice died until after 72 hr.Our data indicate that under some circumstances irradiated LPS can be more safely administered to animals with compromised resistance than can unirrudiated LPS.