The lungs of individuals with alpha(1)-antitrypsin (alpha(1)-AT) deficiency have a reduced antiprotease protective shield. Typically, numbers of neutrophils are elevated in the lungs of affected individuals, carrying large amounts of neutrophil elastase (NE) and alpha-defensins that are released upon activation. We hypothesized that in individuals with advanced lung disease associated with alpha(1)-AT deficiency cytotoxic concentrations of alpha-defensins might be present and unopposed, thus further aggravating lung disease. To evaluate this hypothesis, bronchoalveolar lavage was performed in 20 alpha(1)-AT deficient individuals with moderate to severe lung function impairment and 13 healthy volunteers. Cell counts as well as concentrations of NE and alpha-defensins were determined. While concentrations of NE were low (23+/-14nM) and alpha-defensins were undetectable in volunteers, they were significantly elevated in individuals with alpha(1)-AT deficiency (1313+/-723nM and 6605+/-2856nM, both p<0.0001). These concentrations were significantly higher than those found in a historical control of alpha(1)-AT deficient individuals with mild lung disease. Neutrophil numbers and NE concentration correlated with alpha-defensins concentration (r=0.612 and r=0.758, p=0.005 and p=0.0001, respectively). Individuals with alpha(1)-AT deficiency and moderate to severe lung function impairment have lung alpha-defensins concentrations in a range known to induce cytotoxicity in vitro in the absence of normal amounts alpha(1)-AT and thus may contribute to the development of lung disease in this population.