The serum viscosity of diabetic patients has been found to be increased. The elevation averaged 8% above healthy subjects and 6% above nondiabetic patients. The serum viscosity elevation was greater when diabetic sequelae associated with microangiopathy were present. No relation of serum viscosity to age, sex, obesity, duration of disease, or type of treatment was demonstrated. Serum total protein and glucose levels were found to be correlated with serum viscosity, and increases in their serum concentrations were observed in diabetes. Analysis demonstrated that their elevation did not explain either the viscosity increase or the difference in viscosity between diabetics with and without sequelae.Intrinsic viscosity, abbreviated [eta], is a concentration-independent solute property related to molecular shape. [eta] was found to be 7% higher in diabetic than in normal serum. The [eta] difference accounted for at least half of the serum viscosity elevation. The rest of the increase was due to increased serum protein level and increased nonprotein solids, presumably glucose and lipid. Associated with increased [eta] was a decline in albumin: globulin ratio and elevation of the acute phase reactant proteins, alpha(1)-acid glycoprotein, alpha(1)-antitrypsin, haptoglobin, and ceruloplasmin. Studies comparing diabetic and normal serum fractionated by using 21.5% sodium sulfate showed that changes in [eta] were attributable to changes in serum protein composition rather than an inherent qualitative disturbance of protein present in one of the fractions. Since serum viscosity is elevated in early diabetes, it may be a part of the metabolic disturbance of diabetes and could play a role in the development of diabetic microangiopathy.