Systemic administration of recombinant human interleukin-1 receptor antagonist (IL-1Ra) caused a rapid and sustained elevation of plasma IL-1Ra levels and decreased the leak of intravascularly injected 125I-labeled albumin into lungs of rats given human recombinant interleukin-1 intratracheally. IL-1Ra treatment decreased leak when given 0.5 h before, 1.25 h after, or 2.5 h after IL-1 administration. Similarly, IL-1Ra treatment decreased lavage leukocytes and neutrophils when given 0.5 h before, 1.25 h after, or 2.5 h after IL-1 administration. Pretreatment with IL-1Ra also decreased lung myeloperoxidase activity and breath H2O2 concentration increases in rats given IL-1 intratracheally. Our results suggest that IL-1Ra treatment may decrease acute lung injury and neutrophil influx even when given after an IL-1 inciting insult.