High exposures of Vietnam veterans to 2,3,7, 8-Tetrachlorodibenzo-p-dioxin, a dioxin contained in the herbicide mixture Agent Orange, have previously been demonstrated to be associated with an increased prevalence of diabetes and hyperinsulinemia in non-diabetic subjects. Sixty-nine persons were identified who were in good health and had normal glucose levels during glucose tolerance testing. These subjects lived within 25 miles of the Vertac/Hercules Superfund site located in Jacksonville, Arkansas. The blood sera lipid concentrations of TCDD for the 69 subjects ranged between 2 and 94 ppt. When subjects with blood sera lipid TCDD levels in the top 10% (TCDD > 15 ppt, n = 7) were compared to subjects with lower levels (2-15 ppt, n = 62), there were no group differences in age, obesity, gender distribution, total lipids, or glucose levels. However, plasma insulin concentrations, at fasting and 30, 60, and 120 min following a 75 g glucose load, were significantly higher in the group with high blood TCDD levels. These finding could not be explained by other known risk factors for hyperinsulinemia. The finding of the TCDD-hyperinsulinemia relationship is consistent with studies of Vietnam veterans and suggests that high blood TCDD levels may cause insulin resistance.