Considerable antigenic heterogeneity has been identified among Haemophilus influenzae immunoglobulin A1 (IgA1) proteases, and this study increases the number of antigenic types to more than 30. To address the role played in vivo by this polymorphism, sequential H. influenzae isolates from three healthy children and three patients with chronic obstructive pulmonary disease (COPD) were examined. Healthy children showed a frequent clonal exchange, with each replacing clone expressing an antigenic type of IgA1 protease not previously encountered. In contrast, COPD patients were colonized by a single clone for a significantly longer period. In one COPD clone, a change occurred in IgA1 protease cleavage specificity and antigenic properties. In conclusion, frequent exchange of clones expressing antigenically different IgA1 proteases seems to be the principal mechanism by which H. influenzae evades the immune response of healthy children against IgA1 protease. The results support the view that IgA1 protease activity is important for successful colonization of H. influenzae on mucosal membranes.