The emphysema associated with the inherited serum deficiency of alpha 1-antitrypsin appears to result from an imbalance between neutrophil elastase and its major inhibitor within the alveolar structures. In the present study we assessed the feasibility of reversing this biochemical defect within the lung via parenteral replacement therapy with an alpha 1-antitrypsin concentrate of normal plasma. A 20--40% polyethylene glycol precipitate of pooled human donor plasma was used to obtain an enriched alpha 1-antitrypsin concentrate devoid of hepatitis B antigen and immunoglobulins. Using this material, five individuals with severe serum alpha 1-antitrypsin deficiency (PiZ phenotype) and advanced emphysema received 4 g of alpha 1-antitrypsin intravenously at weekly intervals for four doses. During this period of weekly replacement therapy alpha 1-antitrypsin serum levels were maintained at greater than or equal to 70 mg/dl, the level likely required for effective antielastase protection of the lung. In addition, assessment of lower respiratory tract antielastase activity by bronchoalveolar lavage demonstrated that parenteral replacement of alpha 1-antitrypsin resulted in establishment of effective antielastase activity within the alveolar structures. There were no untoward side effects consequent to this approach to the replacement therapy of alpha 1-antitrypsin. These results demonstrate that the parenteral replacement of alpha 1-antitrypsin provides a means of obtaining elastase-antielastase balance within the lung of individuals with this serum protease inhibitor deficiency.