Previous studies have shown that the underlying patterns of lung injury influence subsequent responses to aerosolized exogenous surfactant. The purpose of this study was to compare aerosolized versus tracheally instilled surfactant in a nonuniform lung injury. Adult sheep underwent whole lung lavage with subsequent HCl instillation into the right middle lobe (RML) and lingula (LING) to create a nonuniform injury. Animals were treated with either nebulized surfactant (Neb.Surf.), tracheally instilled surfactant (Inst.Surf.), or nebulized saline (Neb. Saline). PaO2, alveolar-arterial O2 gradient (PAO2-PaO2), PaCO2, and peak inspiratory pressure (PIP) values all significantly improved during 180 min of continuous aerosolization for Neb.Surf. animals compared with pretreatment values (p < 0.01) and with the other two treatment groups (p < 0.01). Although PaO2 and (PAO2-PaO2) values improved for the Inst.Surf. group by 180 min after treatment (p < 0.05), PaCO2 and PIP values were significantly increased 30 min after surfactant instillation (p < 0.05). Neb. Saline animals had no significant changes in physiologic parameters over 180 min. Approximately 8% of the total aerosolized surfactant deposited in lung tissue was recovered from the more severely damaged RML and LING, compared with approximately 50% of the total instilled surfactant recovered from these lobes. This resulted in significantly greater percentages of the total aerosolized surfactant deposited in each of the remaining lobes compared with the percent deposition of instilled surfactant (p < 0.05). Both the underlying pattern of lung injury and the exogenous surfactant delivery technique may influence clinical responses to surfactant therapy in patients with the adult respiratory distress syndrome (ARDS).