In cystic fibrosis (CF) neutrophil released serine proteinase activity may facilitate Pseudomonas aeruginosa lung colonization, leading to chronic infection. Since such activity is mostly controlled by alpha 1-antitrypsin (alpha 1-AT), we postulated that with CF carrying deficient alpha 1-AT variants might be at higher risk for P. aeruginosa acquisition and might reveal other phenomena, specific for serine proteinase activity. In 215 Danish patients with CF, homozygous (80%) or heterozygous (20%) for the major CF mutation deltaF508, alpha 1-AT variants were determined. Carriage of deficient alpha 1-AT variants was correlated to an earlier onset of P. aeruginosa lung infection (P < 0.0001), higher total IgG (P < 0.0001), and P. aeruginosa-specific serum antibodies (P < 0.0001). The two groups did not differ in lung function, probably due to intensive antimicrobial treatment.