Twenty neonates requiring mechanical ventilation for respiratory failure, including 13 with hyaline membrane disease, were studied to assess the effects of alterations in ventilator settings on mean airway pressure (MAP), blood gases, and intracranial pressure (ICP). The study involved random alterations in peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), and inspiratory/expiratory ratio while MAP, PaO2, ICP, and end-tibal PCO2 were continuously monitored. The results showed a significant relationship between MAP and PaO2 that was expressed as the change in PaO2 per millimeter of mercury change in MAP (delta PaO2/delta MAP) with a mean delta PaO2/delta MAP of 4.92. The delta PaO2/delta MAP was highest for changes in PEEP (6.08), followed by PIP (5.07), and inspiratory/expiratory ratio (1.9). There was a significant relationship between alterations in PEEP and PIP vs PaCO2 and pH. Increases in PEEP and decreases in PIP resulted in an elevated PaCO2 and a lowered pH, and decreases in PEEP and increases in PIP resulted in a decreased PaCO2 and an elevated pH. There was no significant relationship between MAP and ICP, but there was a significant association between delta ICP and delta PaCO2 during alterations in PIP (r = .64, P less than .001). Increases in PEEP will lead to the greatest increase in PaO2 per change in MAP, followed by increase in PIP and inspiratory/expiratory ratio using a pressure-limited ventilator.