Oxyhemoglobin dissociation curves (ODC) from zero to full saturation were developed from tests performed on whole blood from various groups of diabetic and nondiabetic healthy subjects. P50 at in-vivo pH was slightly but significantly lower than normal in ambulatory nonacidotic, uncomplicated juvenile diabetics (26.0 vs. 27.3 mm. Hg, P less than 0.001), despite increased red cell 2,3-diphosphoglycerate (2,3-DPG) concentrations in diabetic erythrocytes (15.0 vs. 13.7 mumole/gm. Hb, P less than 0.001). This combination of changes is in keeping with the presence of increased proportions of hemoglobin AIc in insulin-treated diabetics. The position of the ODC was positively correlated with the 2,3-DPG concentration (P less than 0.01), which varied in response to fluctuations in plasma concentration of inorganic phosphate (Pi) (P less than 0.001). Optimal metabolic control may lead to a normalization of the ODC in association with increased concentrations of red cell 2,3-DPG and P. When the diabetes was uncontrolled, the ODC was usually unchanged during the acidotic phase because the lowered pH balanced the effect of diminished 2,3-DPG concentration on the ODC. After correction of acidosis, the disproportion between erythrocyte 2,3-DPG and pH became quite prominent, accompanied by a corresponding fall in P50 (21.0 vs. 26.1 mm. Hg, P less than 0.001). Following ketoacidosis, with a persistently lowered Pi, it may take up to one week for 2,3-DPG to return to an approximately normal level, and the P50 will be impaired for the same period. A diphosphonate (EHDP) known to enhance tubular phosphate reabsorption in man was given to nonacidotic insulin-treated diabetic and healthy volunteers for 28 days. It caused a significant increase in mean Pi and P50 in both healthy and diabetic subjects (r = 0.58, P less than 0.01). When a dietary supplement of dibasic calcium phosphate was given to diabetic subjects for 28 days, a significant increase in P50 also occurred (25.2 vs. 27.2 mm. Hg, P less than 0.001). It is recommended that the diabetes diet be supplemented by dibasic calcium phosphate to prevent the inhibitory effect of a low concentration of Pi on red cell oxygen delivery.