The polymorphonuclear leukocyte (PMN) may play an important role in the pathogenesis of lung disease associated with cigarette smoking. To investigate its potential for oxidant-mediated lung injury in cigarette smokers, we studied PMN oxidative metabolism in asymptomatic cigarette smokers and nonsmoking control subjects. We found a marked increase in oxidant release in a group of cigarette smokers. After stimulation by phorbol myristate acetate, release of superoxide anion (O-2) by PMN in smokers with white blood counts (WBC) greater than 9,000 was 50% greater than in nonsmokers with similar WBC or smokers and nonsmokers with WBC less than 9,000. Abstinence from smoking did not affect the alterations in O-2 release nor did a serum factor appear responsible. The changes appeared to be part of a generalized increase in oxidative metabolism, as there was greater oxidation of glucose (1-14C) and chemiluminescence by PMN from smokers with WBC greater than 9,000. A further estimate of lung oxidant load was determined by evaluating the marginated pool of PMN. Smokers with WBC greater than 9,000 showed a 70% increase in WBC after epinephrine, and PMN oxidative metabolism remained increased in this group. This study demonstrates that cigarette smokers with elevated WBC have increased release of potentially toxic oxygen metabolites. These cigarette smokers also demonstrated increased oxidant release from the marginated PMN pool. Because leukocyte-generated oxygen metabolites are highly reactive and can cause tissue injury, these findings may have important implications in the pathogenesis of smoking-related lung disease.