OBJECTIVES: Our goal was to evaluate changes in respiratory pattern among premature infants born at <29 weeks gestation who underwent a physiological challenge at 36 weeks postmenstrual age with systematic reductions in supplemental oxygen and inspired airflow. STUDY DESIGN: Subjects were all infants enrolled in the Prematurity and Respiratory Outcomes Project at St. Louis Children's Hospital and eligible for a physiological challenge protocol because they were receiving supplemental oxygen or augmented airflow alone as part of their routine care. Continuous recording of rib cage and abdominal excursion and haemoglobin oxygen saturation (SpO2%) were made in the newborn intensive care unit. RESULTS: 37 of 49 infants (75.5%) failed the challenge, with severe or sustained falls in SpO2%. Also, 16 of 37 infants (43.2%) who failed had marked increases in the amount of periodic breathing at the time of challenge failure. CONCLUSIONS: An unstable respiratory pattern is unmasked with a decrease in inspired oxygen or airflow support in many premature infants. Although infants with significant chronic lung disease may also be predisposed to more periodic breathing, these data suggest that the classification of chronic lung disease of prematurity based solely on clinical requirements for supplemental oxygen or airflow do not account for multiple mechanisms that are likely contributing to the need for respiratory support.