The concentration of high density lipoproteins (HDL) in patients with diabetes mellitus is highly variable. Subnormal HDL cholesterol levels are present in untreated patients with insulin-deficient juvenile diabetes, but the values return to the normal range after beginning insulin therapy. During conventional subcutaneous insulin treatment the diabetic patients often exhibit increased mean HDL cholesterol concentrations, even in the presence of poor diabetic control. HDL concentration is not related to blood glucose or fast hemoglobin levels. However, in the presence of overt ketoacidosis and upon development of advanced diabetic nephropathy, HDL levels fall. In noninsulin-dependent diabetes low HDL cholesterol values are common, but they are associated more with obesity and hypertriglyceridemia than with the diabetic state itself. Thus, when diabetic and nondiabetic subjects are compared at similar relative body weight and serum triglyceride levels, there seems to be no difference in the mean HDL cholesterol values. The possible effects on HDL of treatment by diet and particularly by oral antidiabetic agents are not yet clear; published results are controversial in this respect. Alterations of HDL in diabetes are probably based on the presence of insulin deficiency or, more commonly, on hyperinsulinemia and insulin resistance. HDL (particularly the subfraction HDL2) concentration is regulated by two endothelial lipolytic enzymes, lipoprotein lipase and hepatic lipase, both of which are insulin sensitive. Peripheral hyperinsulinemia is produced in insulin-dependent diabetics by insulin treatment. This results in an increase of tissue lipoprotein lipase activity, which in turn augments HDL levels. In obese diabetic patients the peripheral tissues are resistant to insulin and, accordingly, the lipoprotein lipase activity is subnormal. Furthermore, the hepatic lipase activity is often increased and may contribute to the lowering of HDL by increased removal of HDL cholesterol. It is not known whether the alterations of HDL play any role in the increased atherosclerosis of diabetic patients.