Cumulative damage to lung tissue by leukocyte elastase is thought to be responsible for the development of pulmonary emphysema, an irreversible lung disease characterized by loss of lung elasticity^1–3. It is also thought to be involved in the rapidly developing and usually fatal adult respiratory distress syndrome⁴. The primary defence against elastase damage is the anti-protease known as α₁-antitrypsin^5,6, a glycosylated serum protein of 394 amino acids³. Oxidation of the methionine 358 residue located at the active centre of α₁-antitrypsin results in a dramatic decrease in inhibitory activity towards elastase which effectively inactivates the protective function⁶. It has been suggested that this oxidation sensitivity has a regulatory function and allows tissue breakdown at sites of inflammation by inactivation of α₁-antitrypsin by oxygen radicals released by phagocytes³. In the above diseases, however, the oxidative inactivation of α₁-antitrypsin is probably of major importance in allowing lung damage by elastase^4,7. An oxidation-resistant α₁-antitrypsin might make it possible to reduce the large doses of α₁-antitrypsin required for emphysemics and provide treatment for acute inflammatory respiratory conditions. To further the possibility of therapy for the above conditions, we describe here the synthesis in yeast of active, non-glycosylated, human α₁-antitrypsin. Site-directed mutagenesis has been used to construct an active, oxidation-resistant derivative containing a single methionine to valine substitution at the active centre. This demonstrates the potential of engineered modifications to protein molecules designed to improve their physiological function.