We have previously demonstrated that tumor necrosis factor is involved in the acute toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), since therapies designed to attenuate the effects of tumor necrosis factor resulted in reduced mortality and toxicity in mice exposed to an LD75 dose of TCDD. The current study addresses whether endotoxin may be a contributing factor in the cachexia and mortality resulting from TCDD exposure. Endotoxin-nonresponsive C3H/HeJ mice and endotoxin-responsive C57BL/6 mice were treated with 350 micrograms/kg TCDD and body weight and mortality were recorded. C3H/HeJ mice showed no trend in body weight loss (p = 0.554), while C57BL/6 mice demonstrated a statistically significant (p < 0.01) linear decline in body weight of -0.23 g/day, resulting in a net loss of 3.5 g over 15 days preceding mortality. Mortality was observed in the C57BL/6 mice beginning on day 16 with 100% of the mice dying by the 23rd day while no mortality was observed in C3H/HeJ mice until the 24th day of the study with only 22% mortality observed. These data further demonstrate that endotoxin is a contributing factor to the cachexia and lethality of TCDD.