Secretory leukocyte protease inhibitor (SLPI) is a potent proteinase inhibitor produced in the lung. Stimulated neutrophils at sites of inflammation can inactivate SLPI by myeloperoxidase-mediated oxidation of the methionine residue in the active site of SLPI. Apocynin is a selective inhibitor of NADPH oxidase and may therefore protect SLPI against neutrophil-mediated oxidative inactivation. The aim of the present study was to determine the effect of apocynin on the efficacy of SLPI in preventing experimental emphysema. To investigate the effect of apocynin on emphysema without SLPI treatment, three groups of eight hamsters each received drinking water containing apocynin at concentrations of 2, 20, and 200 micrograms/ml, respectively. Emphysema was induced in these hamsters by intratracheal instillations of 500 micrograms of lipopolysaccharide (LPS) twice a week for 4 wk. In hamsters that received 200 micrograms/ml apocynin, the development of emphysema was reduced by 26.2% (p = 0.01). Other apocynin concentrations had no effect. The experiment was repeated, with SLPI added to the treatment. Of a total of six groups of hamsters, four groups (three with apocynin and one with solvent) received twice-weekly doses of a mixture of 500 micrograms of LPS and 1 mg SLPI in 200 microliters saline in the trachea for 4 wk. In addition, each LPS instillation was followed 24 and 48 h later by an instillation containing 1 mg of SLPI. Apocynin (20 and 200 micrograms/ml) improved the protective effect of SLPI from 37 to 64% and 79%, respectively (p < 0.01). We conclude that oral administration of apocynin can improve the efficacy of SLPI in preventing LPS-induced emphysema.