Abstract. Objective: To evaluate the effects of brief systemic hypoxia on cerebral tissue saturation in premature infants with respiratory disease. We hypothesized that healthy premature infants have a direct relationship between arterial oxygen saturation (SpO2) and cerebral oxygen saturation (SctO2) and that the nature of the relationship is associated with demographic markers of maturation. Furthermore, we hypothesized that most infants can maintain adequate cerebral tissue saturation during brief periods of systemic hypoxia. Study design: Twenty-four preterm neonates with respiratory disease were enrolled and monitored for 72 hours using simultaneous pulse oximetry (to detect SpO2) and cerebral tissue oximetry (to detect SctO2). The relationship between SpO2 and SctO2 and demographic markers of maturation were analyzed, using linear and non-parametric regression methods. Result: As expected, SctO2 decreased linearly with decreased SpO2. The drop rate of SctO2 significantly increased in relation to SpO2 with decreasing gestational age, corrected gestational age and weight (both birth weight and weight at time of study) but not post-natal age. Conclusion: Healthy premature infants with isolated respiratory disease can maintain adequate cerebral tissue saturations during periods of brief hypoxemia without requiring additional intervention. Each infant has a unique ability to regulate cerebral oxygenation, which appears to be associated with advancing gestational age and increasing weight.