The right-shifted oxyhemoglobin dissociation curve of sickle cell disease (SCD) has been thought to result in abnormally low arterial oxygen saturation (S(o)(2)), even when oxygen partial pressure (P(o)(2)) is normal. However, without polymer formation (minimal under normoxic conditions), HbS oxygen affinity is normal. We hypothesized that in SCD, in vivo S(o)(2) is normal when P(o)(2) is normal. We retrospectively examined 50 blood gas and COoximetry samples from SCD patients and from controls matched for pH, P(o)(2), and carboxyhemoglobin. Control data fell close to the Severinghaus curve, as did non-hypoxemic ( [Formula: see text] ) SCD data. In contrast, hypoxemic (S(o)(2)) < 92.5% SCD data fell well below the standard curve. Thus, although SCD patients' oxygen affinity is low under hypoxic conditions, it is normal at normal arterial S(o)(2). Therefore, a finding of abnormally low saturation demonstrates that P(o)(2) is abnormally low. Given our previous finding that pulse oximetry faithfully reflects saturation in SCD, low pulse oximeter readings in SCD constitute reliable evidence of impaired gas exchange.