The primary function of α₁-antitrypsin (α₁-AT), an antiprotease produced by the liver, is the inhibition of neutrophil elastase, a protease capable of hydrolysing most connective tissue components^1–4. The importance of α₁-AT is demonstrated by the high incidence of early-onset emphysema in individuals with hereditary α₁-AT deficiency (Type PiZZ), in whom serum levels of α₁-AT are 10–20% of normal^5–10. Oxidants in tobacco smoke can inactivate α₁-AT in vitro^11,12, and studies have shown that α₁-AT from the lungs of individuals who smoke cigarettes may also be partially inactivated, perhaps explaining the high incidence of emphysema associated with cigarette smoking^13,14. Oxidative inactivation is probably due to modification of the Met residue (Met³⁵⁸) at the P1 subsite position of the elastase binding site of the protein^15,16. To study the possibility of modulating the biological properties of α₁-AT, we have introduced selected sequence modifications at the reactive site by in vitro mutation of a cloned α₁-AT complementary DNA. We describe here the characterization of two α₁-AT analogues produced in Escherichia coli. The first, α₁-AT(Met³⁸⁵→Val), is not only fully active as an elastase inhibitor but is also resistant to oxidative inactivation. The other, α₁-AT(Met³⁵⁸→Arg), no longer inhibits elastase but is an efficient thrombin inhibitor. The active site of the latter is identical to that of the α₁-AT (Pittsburgh) variant, which was associated with a fatal bleeding disorder^17,18.