The hereditary disorder alpha 1-antitrypsin (alpha 1AT) deficiency results in the development of emphysema due to a diminished anti-neutrophil elastase screen of the lower respiratory tract. Specific therapy for this disorder is available in the form of weekly intravenous infusions of human plasma alpha 1AT, which effectively reconstitute the anti-elastase screen of the lung in these individuals. In an attempt to reduce the frequency of therapy we evaluated the ability of monthly infusions of alpha 1AT to provide equivalent lower respiratory tract protection against neutrophil elastase. Intravenous infusion of 250 mg/kg of alpha 1AT at 28-day intervals to nine individuals with alpha 1AT deficiency and emphysema was carried out for 12 months. Serum alpha 1AT levels exceeded the protective threshold for an average of 25 days after each dose of alpha 1AT was administered. Furthermore, the postinfusion level of alpha 1AT in the nadir lung epithelial lining fluid was fivefold greater than the preinfusion level, and the anti-neutrophil elastase capacity of the nadir epithelial lining fluid also was elevated significantly, nearly threefold above the preinfusion level. These results indicate that monthly administration of human alpha 1AT is fully capable of adequately augmenting serum and lung alpha 1AT levels and anti-elastase capacity and is therefore a rational alternative to weekly therapy.