Male Sprague‐Dawley rats were given a single, usually lethal, dose of 2,3,7,8‐tetra‐chlorodibenzo‐p‐dioxin (TCDD, 125 μg/kg ip in corn oil), or vehicle alone. Twenty‐four hours after ip administration of TCDD the animals received an ip injection of14C‐labeled glucose, and the time course and amount of exhalation of14CO2were monitored for 8 h continuously and once daily for 20 min for the subsequent 5 d. TCDD treatment reduced the amount of14CO2exhaled within 8 h after the injection of [14C]glucose by 33%, as compared to pair‐fed controls. Blood levels of radioactivity were affected by TCDD accordingly. No particular organ appeared to act as a sink for the radioactivity not exhaled during these 8 h by the treated animals. TCDD (125 μg/kg) induced significant changes in the disposition of radioactivity in heart and brown adipose tissue between 25 and 125 min after the iv injection of [14C]glucose. The areas under the curve of [14C]glucose‐derived radioactivity were the same after either iv or ip injection in the blood of TCDD‐treated rats, allowing a direct comparison of experiments with iv or ip injection of [14C]glucose. The half‐lives of radioactivity in the exhaled air and in feces of treated animals were greatly elevated during the 5 d following administration of [14C]glucose. These results indicate that TCDD induces in rats, within 24 h after dosing, alterations in the metabolism of glucose that preceded changes in insulin homeostasis, because hypoglycemia and hypoinsulinemia in rats do not occur until about a week after TCDD treatment. Since overt signs of acute toxicity (reduced feed intake and body weight loss) are also not noticeable until several days after a lethal dose of TCDD, it is probable that this earlier disturbance of glucose metabolism is part of the biological changes that result in wasting away and eventually in death.