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This prospective clinical study evaluated the influence of high bilirubin plasma levels on the Nellcor® pulse oximeter readings (Spo2). Twenty-nine icteric patients (mean total bilirubin 19.2 mg/dl, range 2.3–84.3 mg/dl) were compared with 46 controls. The difference between Spo2 and oxyhemoglobin percentage of hemoglobin (Hbo2corr) or fractional saturation as measured by a seven wavelengths Corning Co 2500 Co-oximeter® and corrected for the spectral error induced by hyperbilirubinemia in that co-oximeter was greater in icteric patients (bias and precision: 2.9% ± 2.2% vs. 1.7% ± 2.7%, P < 0.03). However, icteric patients had also higher corrected carboxyhemeglobin levels (CoHbcorr) (1.8% ± 0.7% vs. 1.3% ± 0.8%, P < 0.005) due to production of carbon monoxide during the catabolism of hemoglobin. Pulse oximeters read most of CoHb as oxyhemoglobin. After correcting Spo2 for carboxyhemoglobin in both groups of patients, the 99% confidence limits from the obtained regression line were the same in icteric patients (–0.81%, 1.03%) as in controls (–0.89%, 1.08%). There was thus no demonstrable direct influence of high bilirubin plasma levels on Spo2 as measured by a Nellcor® pulse oximeter.