Surfactant treatment has become the standard of care in premature infants with respiratory distress syndrome (RDS). Pulmonary hemorrhage, pulmonary edema, pneumonia, and atelectasis have been shown to liberate inflammatory mediators and plasma proteins, which damage type II pneumocytes and inactivate surfactant. These disease processes may, therefore, lead to a secondary surfactant inactivation or deficiency, which can be an unrecognized cause of respiratory decompensation after initial recovery from RDS in this vulnerable population. This is a descriptive report of three cases, which had acute respiratory decompensation between 1 and 3 weeks of age. All three infants demonstrated a response to secondary doses of surfactant. We submit that the diagnosis and treatment of secondary surfactant deficiency in the critically ill premature neonate warrants further study.