Pulmonary complications and hypoxemia are common in sickle cell disease (SCD) and may exacerbate microvascular occlusive phenomena. Thus, detecting hypoxemia is of particular importance in SCD. To assess the accuracy of pulse oximetry in the diagnosis of hypoxemia in SCD, we compared 22 pulse oximetric measurements of arterial oxygen saturation (SpO2) in adult patients with SCD and acute vasoocclusive crisis with simultaneously drawn arterial saturation (SaO2 = oxyhemoglobin divided by oxyhemoglobin plus reduced hemoglobin) measured by co-oximetry. We accepted SpO2 readings only if they were stable and characterized by strong and regular photoplethysmographic waves on the oximeter screen. To assess the position of these patients' oxyhemoglobin dissociation curves, we plotted arterial and venous oxygen saturation (SaO2 and SvO2 ) against oxygen tension. We found right-shifted oxyhemoglobin dissociation curves, with pH-corrected p50s ranging from 28 to 38 mm Hg. Pulse oximetry slightly overestimated oxyhemoglobin percentage (by an average of 3.4 percentage points), but it almost always accurately estimated SaO2 (underestimating on average by 1.1 percentage points). The error in SpO2 was never enough to classify a hypoxemic patient erroneously as normoxemic or a normoxemic patient as hypoxemic. We conclude that, as long as strong and regular photoplethysmographic waves are present, pulse oximeters can be relied upon not to misdiagnose either hypoxemia or normoxemia in SCD.