OBJECTIVES:To ascertain the potential effects of hypoxemia and race on pulse oximetry in a population of patients, including those for whom hypoxemia is a normal state secondary to intracardiac mixing in an ICU setting. DESIGN:Retrospective, observational, cohort study. SETTING:A single center's pediatric cardiac ICU (CICU). PATIENTS:Eight hundred forty-one patients undergoing bypass operations during a 52-month period (June 2019-October 2023). Predominantly, patients with congenital heart disease. The median age was 7.1 months with 58% younger than 1 year old and 88% younger than 10 years old. INTERVENTIONS:Arterial blood saturations, as measured by a hemoximeter, were recorded for all patients after bypass operations. These were time-matched, with high-fidelity, to pulse oximeter values. MEASUREMENTS AND MAIN RESULTS:The mean oximetric difference, or "pulse oximetry overestimation," was defined as arterial oxygen saturation minus that predicted by pulse oximetry, was greater for Black than for White patients (-3.18% vs. -2.19%, p = 0.006). Regression shows a significant effect of Sao2 on oximetric difference (p < 0.001) and mildly significant trend for the categorical race (p = 0.03) as well as their composite interaction term (p = 0.047). Oximetric difference was exaggerated with increasing hypoxemia. At normal oxygen saturations, the oximetric difference was greater for Black when compared with White patients (p = 0.002 for patients with Sao2 > 94%). This effect if race is not statistically significant at other Sao2 ranges that are clinically important in patients with intracardiac mixing. CONCLUSIONS:This study redemonstrates effect of increasing hypoxemia on oximetric difference. Race may have an independent effect on oximetric difference. This adds to the body of literature that has previously suggested that pulse oximetry, relied upon as a vital sign, may introduce explicit race-related bias into the bedside interpretation of a patient's clinical state.