The plasma levels of protein C were investigated in 54 type I diabetic patients without retinopathy and in 14 diabetic patients with diabetic retinopathy and compared with the findings in 35 sex- and age-matched healthy control subjects. In the total group of type I diabetic patients, protein C was significantly less than in the controls. The lowest levels of protein C were found in diabetic patients with the poorest metabolic control. Protein C levels showed a significant negative correlation with the blood glucose levels, but they were not correlated with hemoglobin A_1c (HbA_1c). Although patients with retinopathy showed the least decrease of the plasma level of protein C among the diabetic subjects, the ratio of protein C to factor II was significantly decreased compared with the control subjects. Because the levels of coagulation factor II were not reduced in diabetic patients, the reduction of protein C seems to be caused, not by reduced synthesis in the liver, but more likely by an increased clearance from the blood plasma. The decrease of protein C in the plasma of type I diabetic patients indicates an abnormal, probably hypercoagulable, hemostatic situation in this disorder.