SUMMARY: Secretory leukocyte inhibitor (SLPI) is a potent inhibitor of serine proteinases, but sensitive to oxidative inactivation due to a methionine residue in the active centre of the inhibitor. We compared the potency of an oxidation-resistant mutant of recombinant SLPI with native recombinant SLPI in lipopolysaccharide (LPS)induced emphysema in the hamster. Application of this oxidation-resistant mutant reduced the induced emphysema by 70 and (85 %) in two separate series of experiments. In contrast, an equal amount of native rSLPI resulted in significantly lower inhibition, 30 and (23 %), respectively ((P=0.002)). To demonstrate the effect of oxygen radicals upon a single LPS instillation in the lungs, we measured anti-neutrophil elastase activity in lung lavage fluid at 10 and (24 \mathrm{~h}) after the instillation of a mixture of LPS and native rSLPI. We found that residual native rSLPI was only 70 and (55 %) active, respectively. The rSLPI-mutant remained (93 %) active in a similar experiment. The native and mutant inhibitor showed equal potency against proteinases in a granule extract of hamster neutrophils. We conclude that the replacement of methionine by leucine in the inhibitory centre of rSLPI results in a decreased sensitivity to oxidative inactivation and that this alone is sufficient to explain the greater efficiency of the rSLPI-mutant in reducing the extent of LPS-induced emphysema.