Decreased deformability of neutrophils exposed to cigarette smoke is considered a determinant of neutrophil sequestration within the pulmonary microvasculature, which may be a risk for the development of pulmonary emphysema. In this study we examined the effect of nicotine, a major cigarette component, on the reduction in neutrophil deformability, measured as cell filterability, after exposed to cigarette smoke. Neutrophils were exposed to smoke by incubating them in an aqueous solution of smoke extracts. Filterability of neutrophils was studied by a vertical filtration technique by measuring their ability to pass through a micropore membrane and expressed as membrane resistance. There was a negative relationship between membrane resistance after exposure to whole smoke and the nicotine content of the cigarettes tested. Whole smoke increased the membrane resistance less than gas-phase smoke, from which almost all nicotine had been excluded. Addition of nicotine, glutathione, alpha-tocopherol, thymol, and erythrocytes prevented the increase in membrane resistance following gas-phase smoke exposure. Nicotine also protected against an increase in membrane resistance against the effect of chloramine-T and hydrogen peroxide, but it provided no protection from superoxide radical generated from a xanthine-xanthine oxidase mixture of N-formylmethionylleucylphenylalanine. These results suggest that nicotine prevents the reduction in neutrophil filterability, probably by scavenging oxidants present in the cigarette smoke.