The bacterial immunoglobulin A1 (IgA1) proteases are putative virulence factors secreted by a number of human pathogens capable of penetrating the mucosal barrier. Among Haemophilus influenzae strains, the IgA1 protease is found in several allelic forms with different serological neutralizing properties. A comparison of the primary structures of four serologically distinct H. influenzae IgA1 proteases suggests that this variation is caused by epitopes of the discontinuous conformational type. Analysis of the homologies among the four iga genes indicates that the variation results from transformation and subsequent homologous recombination in the iga gene region among H. influenzae strains. We find evidence for gene rearrangements, including transpositions in the iga gene region encoding the secretory part of the IgA1 preprotease. The amino acid sequence of the C terminus of the preprotease (the beta-core), which is assumed to be involved in secretion of the protease by forming a pore in the outer membrane, is highly conserved. In contrast to conserved areas in the protease domain, the nucleotide sequence encoding the beta-core showed a striking paucity of synonymous site variation.