A single i.p. administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) caused within 1 wk of exposure a dose-dependent progressive inhibition of liver fatty acid synthetic rate with concomitant decreases in hepatic fatty acid synthetase and acetylcoenzyme A carboxylase activities. Similarly, hepatic cholesterol synthetic rate was markedly inhibited with increasing dosage of TCDD, although the corresponding decrease in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was of lesser magnitude. Linear regression analyses of the reciprocals of the responses versus the dose revealed that the TCDD concentration which caused 50% inhibition of the activities of various lipogenic enzymes and of lipid synthetic rates ranged from 11 to 20 micrograms/kg (34-67 nM) with an average of 15 micrograms/kg (47 nM). Hepatic cholesterol synthesis seemed to be more sensitive to inhibition than fatty acid synthesis whether it was based on TCDD dosage or duration of exposure. The degree of inhibition of all the above parameters except fatty acid synthesis in liver and adipose tissues increased from 1 to 2 wk of exposure but was less pronounced after 4 wk exposure. Significantly, the adipose tissue was found to be more sensitive than the liver with respect to inhibition of fatty acid synthesis by increasing dosage of TCDD. Thus, the biochemical mechanism of loss of adipose mass caused by TCDD exposure may well be mediated by strong inhibition of lipid synthesis in the adipose tissue coupled with increased mobilization of depot fat.