Direct exposure of human alpha-1-proteinase inhibitor to the gas-phase smoke from one cigarette results in an initial rapid loss of elastase inhibitory capacity, the amount of which is dependent upon the age of the smoke. This short-term inactivation is not seen when the protein is exposed to aqueous extracts of cigarette smoke (as had been done in the past). Both exposure regimens result in a slow inactivation occurring over several days. We suggest that the short-term inactivation may be due to a peroxynitrate (or a similar reactive species) that is formed from radicals in the gas phase but is unstable in aqueous solution.