Wegener's granulomatosis (WG) is classically associated with the presence of cytoplasmic antineutrophil cytoplasmic autoantibodies (c-ANCA). Proteinase 3 (PR3), the target antigen for c-ANCA, is inhibited by the antiprotease α 1-antitrypsin (A1AT), and recent studies have demonstrated that WG patients who are A1AT-deficient have a worse clinical course, suggesting that a protease–antiprotease imbalance may play a role in WG. We evaluated the effect of A1AT on anti-PR3 antibody–induced activation of neutrophils. The neutrophil was chosen because of its central role in the pathogenesis of WG. Isolated neutrophils from healthy controls were incubated with tumor necrosis factor (TNF)- α to induce surface expression of PR3. Subsequently, they were stimulated with a monoclonal antibody to PR3, resulting in a significant increase in respiratory burst. Addition of A1AT (1 mg/ml) to the TNF- α – primed cells before the addition of the anti-PR3 antibody resulted in a 47% reduction in anti-PR3 antibody–induced activation. A1AT mediated this inhibitory action by preventing anti-PR3 antibody binding to PR3 on the cell, thereby preventing the PR3–Fc γ R11a cross-linkage required for cell activation. Further, anti-PR3 antibody–induced activation of neutrophils from WG patients can be reduced by 56% with A1AT. These data suggest that protease–antiprotease interactions may play a pivotal role in neutrophil activation in WG.