Incubation of highly purified human C1 inhibitor with equally pure human leukocyte proteinase 3, resulted in a dose- and time-dependent inactivation of C1 inhibitor hemolytic activity. Furthermore, this inactivation was accompanied by proteinase 3-dependent cleavage of the C1 inhibitor into an 83,000 molecular weight fragment. The formation of the 83,000 molecular weight fragment followed a time course which was similar to that observed for the inactivation of hemolytic activity. Within 120 minutes more than 90% of the hemolytic activity was lost. This inactivation of C1 inhibitor appeared to be selective as purified human C1q was not degraded in a similar time period. Moreover, when 100 micrograms IgG, isolated from each of 21 Wegener's granulomatosis patients with cytoplasmic anti-nuclear antibodies immunofluorescent titers to proteinase 3 greater then 1:64, was incubated with 3 milliunits of proteinase 3, little to no cleavage of C1 inhibitor was observed. In contrast, 100 micrograms of IgG isolated from 14 normal donors was ineffective in affording protection to C1 inhibitor upon incubation with proteinase 3. Our results suggest that neutrophil infiltration and activation could lead to local complement consumption at the tissue sites.