The association between platelet counts and mechanical ventilation was assessed in 61 newborn infants with respiratory distress syndrome, 10 infants with congenital diaphragmatic hernia, and 10 infants with tracheoesophageal fistula. A significant decrease in platelet counts was observed during mechanical ventilation: (mean +/- SD) reduction of 39% +/- 5%, 42% +/- 5.6%, and 11.9% +/- 5.4% in the three groups, respectively, independent of other causes. In the group with congenital diaphragmatic hernia, there was a significant correlation between mean airway pressure and the reduction in platelet counts. In a subsequent series of experiments, platelet counts were recorded before and during ventilation in rabbits. A significant mean decrease of 37.3% in platelet counts was associated with ventilation with either air or pure oxygen. Results of these studies indicate that mechanical ventilation itself may cause a major decrease in platelet count in newborn infants.