Hemoglobin A in 0.05 M bis-tris buffer was autoxidized under various oxygen pressures from 0.21 (oxygen pressure in air) to 8 atmospheres at pHs 6.5 and 8.5. All experiments were carried out without and with 5 molar excess of inositol hexaphosphate/heme at 37 degrees C. It is shown that increasing the oxygen pressure from 0.21 to 1 atmosphere decreases the autoxidation rate to about 80% whereas increasing the oxygen pressure further to 8 atmospheres has a reverse effect. This phenomenon is observed at both acid and alkaline pHs, although it is less marked at the latter pH. The stimulating effect of inositol hexaphosphate on the autoxidation is abolished at high oxygen pressure. It is suggested that moderate elevation of the oxygen pressure above the atmospheric pressure stabilizes further the hemoglobin R conformation which decreases the autoxidation rate. At very high oxygen pressure, the oxidizing potential of oxygen oxidizes the oxyhemoglobin directly in the R conformation. The maximal shift of hemoglobin T in equilibrium with R conformational equilibrium towards R conformation interferes with the binding of inositol hexaphosphate and hence abolishes its effect.