The vasculitic lesions observed in Wegener's granulomatosis may be partly the consequence of proteases released following activation of neutrophils by ANCA. The activity of these proteases, including proteinase 3 (PR3) and elastase, is normally closely restricted to the inflammation site by a large excess of circulating alpha-1-antitrypsin (alpha1AT). Patients with ANCA-positive systemic vasculitis may exhibit a protease/antiprotease imbalance either genetically determined in the rare patients with deficient alpha1AT phenotypes, or more often acquired through both alpha1AT inactivation in various pathological conditions and possible inhibition of PR3/alpha1AT complexation by anti-PR3 ANCA. This imbalance may at least contribute to disease spreading or aggravation.