Recent findings that hemoglobin S gelation and sickling are pH- dependent and also influence oxygen affinity suggested that the red cells containing this hemoglobin variant might show an abnormal Bohr effect. We therefore studied the effects of pH variation on the in vitro oxygen affinity of whole blood from persons with sickle cell anemia (SS) and normal donors (at 37 degrees C and constant carbon dioxide tension of 40 mm Hg). The Bohr effect in SS blood was greatly increased only between blood pH 7.4 and 7.2 (cell pH 7.2 and 7.0, a shift that strongly affects gelation), with delta log p50/deltapH= - 0.92 to -0.99 (normal = -0.42 to -0.46). Thus a drop in SS blood pH below 7.4 in tissue capillaries yields twice the normal decrease in oxygen affinity and a large release of oxygen from red cells, whose risk of sickling is high. Even mild transient acidosis would seem hazardous for patients with sickling disorders.