The effect of oral disodium ethane-1-hydroxy-1,1-diphosphonate, EHDP (20 mg kg-1 day-1) and placebo given for 28 days on plasma inorganic phosphate (Pi) red cell 2,3-diphosphoglycerate and oxygen affinity of hemoglobin was evaluated in 14 insulin-treated diabetics and 5 healthy volunteers. EHDP significantly increased mean Pi (diabetics: 1.18 to 1.67 mmol/l, p less than 0.01, controls: 1.03 to 1.71 mmol/l, p less than 0.02) and P50 at in vivo pH of the oxyhemoglobin dissociation curve (diabetics: 25.4 to 26.6 mmHg, p less than 0.02; controls: 26.3 to 28.9 mmHg, p less than 0.02). Pi and P50 were correlated in both diabetics and in controls (p less than 0.05). 2,3-DPG increased when the diabetics were on EHDP (p less than 0.005). The study emphasizes the importance of Pi on red cell function and indicates that an elevation of Pi tends to counteract the defect in oxygen release capacity of the red cells in diabetic subjects.