The peripheral metabolism of [3H]estradiol-17 beta (E2(3)H) was studied in ovariectomized, streptozotocin induced diabetic rats, in an attempt to understand the reduced nuclear retention time and the decreased activity on protein synthesis of E2 in diabetic rat uterus as reported recently. E2(3)H was injected intraperitoneally and the kinetics of 3H metabolites were followed in plasma extracts obtained between the time intervals of 10-210 min after injection. Diabetics accumulated about 15 times more ether insoluble metabolites by the tenth minute as compared to the controls. The metabolites contained relatively more glycurono- and less sulfoconjugates in diabetics. After hydrolysis of either fraction, most of the radioactivity migrated as estrone or was less polar than estrone on LH20 column chromatography. Half of the ether insoluble material was not hydrolyzable by Helix pomatia gastric juice. The ether soluble fraction contained more estrone and non polar material, but less estradiol in the diabetics than in the controls. The plasma disappearance rates of all fractions were faster in the diabetics. For estradiol itself, the half life was two to three times shorter in the diabetics after either intravenous or intraperitoneal injection of the tracer. The metabolic clearance rate of E2(3)H measured by constant intravenous infusion was 1746 +/- 326 ml/h and 1136 +/- 347 ml/h in diabetics and controls (P less than 0.001). In conclusion, E2(3)H was cleared much faster from the peripheral circulation in diabetics, resulting in an early accumulation of ether soluble and non soluble metabolites; the latter contained proportionately less sulfo- and more glycuronoconjugates than in the controls. The rapid disappearance of E2 from the plasma of diabetics may play a role in the shorter retention time of the hormone-receptor complex and the reduced activity of the hormone at the uterine level.