C57BL/6 mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 360 micrograms/kg) displayed a significant reduction in feed intake and body weight until just before death, when they developed ascites and subcutaneous edema. This caused body weight of the mice that died to suddenly increase during the terminal stage of toxicity. TCDD-treated mice that survived did not develop ascites or edema, and maintained a body weight that was slightly less than that of pair-fed mice. Cumulative lethality in TCDD-treated mice (69%) was greater than that of pair-fed controls (14%). In guinea pigs treated with TCDD (2 micrograms/kg) both the time course and magnitude of hypophagia were closely associated with weight loss. Pair-fed guinea pigs did not lose quite as much weight as TCDD-treated animals because their total body water content was higher. Water intake in pair-fed guinea pigs was greater than that of TCDD-treated animals. The time course and magnitude of lethality tended to be similar in TCDD-treated guinea pigs (81%) and pair-fed controls (64%). In Fischer F-344 rats treated with TCDD (100 micrograms/kg) body weight loss was associated with a reduction in both feed and water intake. The time course and magnitude of weight loss in TCDD-treated and pair-fed rats was essentially identical. Lethality was higher in TCDD-treated rats (95%) than pair-fed control animals (48%). Taken together, these findings suggest that hypophagia is responsible for the loss of adipose and lean tissue in mice, guinea pigs, and rats treated with a LD70-95 dose of TCDD. Under these dosage conditions, weight loss contributes more to the lethality of guinea pigs than to that of Fischer F-344 rats or C57BL/6 mice.