We found that rats pretreated with interleukin-1 (IL-1) intraperitoneally did not develop the acute oxidative, neutrophil-dependent lung leak that occurs after administration of IL-1 intratracheally (IL-1-induced tolerance). IL-1-pretreated rats also had increased lung catalase and glucose-6-phosphate dehydrogenase (G6PDH) activity and increased plasma catalase activity compared with sham-pretreated rats. In contrast to reducing lung leak, IL-1 pretreatment did not reduce the numbers of neutrophils that are increased in lung lavages of rats given IL-1 intratracheally. IL-1-induced tolerance to IL-1-mediated lung leak and the associated increases in lung catalase, lung G6PDH, and serum catalase activities were all prevented by treating rats with the IL-1-receptor antagonist or with N-acetyl-L-cysteine, an agent that increases intracellular glutathione levels. Our results indicate that IL-1 pretreatment confers tolerance to IL-1-mediated lung leak without decreasing IL-1-induced increases in lung neutrophils. The possible protective actions of IL-1 should be considered in experiments and clinical trials where IL-1 activity is reduced pharmacologically.