The abilities of a number of compounds of biological interest to protect alpha-1-proteinase inhibitor (alPI) against the loss of elastase inhibitory capacity (EIC) resulting from exposure to gas-phase cigarette smoke have been tested. We have identified several species that protect AlPI. Amino acids prevent the loss of EIC in a manner that correlates with their pK alpha-values; only the unprotonated amine provides protection. Catalase partially prevents the loss of EIC, suggesting that hydrogen peroxide produced from the reduction of oxygen in cigarette smoke extracts is responsible for at least some of the smoke-induced inactivation. The best protection against smoke-induced loss of EIC was provided by two biologically important antioxidant species: glutathione and ascorbic acid. Both species provide almost complete protection to alPI under the experimental conditions used. The nature of species that protect AlPI against the inactivation caused by exposure to gas-phase smoke provides clues upon which speculations about the mechanism of this inactivation may be based. The identification of protective species could lead to the development of compounds that smokers could take (for example, vitamin C) that would protect their lung tissue against the oxidative damage caused by cigarette smoke.