The reason for the disproportionately higher level of vascular disease in patients with diabetes is not known. Oxidative modification of low-density lipoproteins has been implicated in impaired cholesterol uptake and its deposition in the arterial wall and atherosclerosis. The present study has examined the effects of hyperketonemia, glycemic control and duration of diabetes on the in vitro oxidative susceptibility to Cu++ of low-density lipoprotein (LDL) + very low-density lipoprotein (VLDL) from 34 Type-I diabetic patients without any clinical sign of vascular disease and 22 age-matched normal individuals. LDL + VLDL was isolated from plasma using a micro-affinity column. LDL + VLDL isolated from diabetic patients and age-matched normal individuals was treated with 25 mM CuCl2 for 1.5, 3 and 5 h. The ketone bodies acetoacetate (AA) and beta-hydroxybutyrate (BHB), as well as glycated hemoglobin (HbA1), were measured in the blood by standard methods. There was no difference in the in vitro oxidative susceptibility of LDL + VLDL at all time periods between Type-I diabetics (n = 34) and age-matched normal individuals (n = 22). However, among diabetics, when patients were separated into normoketonemic (NK) and hyperketonemic (HK) groups, in vitro oxidation of LDL + VLDL at 1.5 h from hyperketonemic diabetics was a 69% greater (p < .02) compared with that of normoketonemic diabetics and 80% greater (p < .02) compared with that of normal individuals. There was a significant correlation (r = 0.38, p < .03) between the in vitro oxidation of LDL + VLDL at 1.5 h and AA levels in diabetic patients. The level of in vitro oxidizability of LDL + VLDL did not have any correlation with levels of BHB (r = 0.20, p > .26), HbA1 (r = 0, p > .99), glucose (r = 0.06, p > .75) or duration of diabetes (r = 0.15, p > .40) in diabetic patients. In vitro incubation of normal plasma with AA resulted in an increase in the Cu + induced lipid peroxidation of LDL + VLDL. This study suggests that frequent episodes of ketosis and elevated levels of AA constitute a risk factor for the oxidative modification of low-density lipoproteins and development of vascular disease in diabetic patients.