Lipemic plasma with marked elevations of plasma triglyceride levels (3221 +/- 1590 mg/dl) and fasting chylomicronemia was observed in nine patients with uncontrolled non-insulin-dependent diabetes mellitus. Every case had hypertriglyceridemic relatives, suggesting that the very high triglyceride values seen resulted from the coexistence of diabetes with a familial form of hypertriglyceridemia. A number of clinical and biochemical features observed in the diabetic patients and also in a group of nondiabetic controls with comparable degrees of hypertriglyceridemia suggests that these manifestations are related to high plasma triglyceride levels rather than to the diabetes per se. Chronic abdominal pain, mental confusion, and memory loss improved with lipid-lowering therapy and clearing the plasma of chylomicrons. Pulmonary function tests, red cell 2,3-diphosphoglycerate, and hemoglobin oxygen affinity were normal; the mild hypoxemia observed is believed to be an artifact. It is suggested that a syndrome due to chylomicronemia can occur in uncontrolled non-insulin-dependent diabetic patients, who in addition have a familial form of hypertriglyceridemia. To prevent manifestations of this syndrome in these patients, specific lipid-lowering therapy may be required in addition to control of their diabetes.