The role of neutrophils in the mediation of severe normobaric hyperoxic lung injury has been studied by monitoring the effects of neutrophil depletion on a rat model of pulmonary oxygen toxicity. Pulmonary capillary permeability, assessed using an [125I]albumin lung permeability index (LPI), progressively increased with an increased duration of hyperoxia exposure in normal animals (LPI = 0.43 +/- 0.09 at 24 h; 0.95 +/- 0.17 at 48 h; 1.56 +/- 0.21 at 60 h), despite the absence of any significant tissue or bronchoalveolar lavage evidence of neutrophil infiltration until 60 h of hyperoxia exposure. Neutrophil depletion (using cyclophosphamide) blocked this late neutrophil infiltrate but failed to attenuate lung injury (LPI = 0.38 +/- 0.06 at 24 h; 0.89 +/- 0.16 at 48 h; 1.58 +/- 0.10 at 60 h; all p greater than .05 compared with leucocyte-replete/normal animals exposed to hyperoxia). The temporal dissociation of pulmonary neutrophil accumulation and pulmonary injury and the failure of effective neutrophil depletion to abrogate hyperoxic lung injury indicate that neutrophil polymorphs play no substantive role in the mediation of tissue injury in this model of severe pulmonary oxygen toxicity.