The role of tumor necrosis factor-α (TNF-α) as a mediator of cigarette smoke–induced disease is controversial. We exposed mice with knocked-out p55/p75 TNF-α receptors (TNF-α–RKO mice) to cigarette smoke and compared them with control mice. Two hours after smoke exposure, increases in gene expression of TNF-α, neutrophil chemoattractant, macrophage inflammatory protein-2, and macrophage chemoattractant, protein-1 were seen in control mice. By 6 hours, TNF-α, macrophage inflammatory protein-2, and macrophage chemoattractant protein-1 gene expression levels had returned to control values in control mice and stayed at control values through 24 hours. In TNF-α–RKO mice, no changes in gene expression of these mediators were seen at any time. At 24 hours, control mice demonstrated increases in lavage neutrophils, macrophages, desmosine (a measure of elastin breakdown), and hydroxyproline (a measure of collagen breakdown), whereas TNF-α–RKO mice did not. In separate experiments, pure strain 129 mice, which produce low levels of TNF-α, showed no inflammatory response to smoke at 24 hours or 7 days. We conclude that TNF-α is central to acute smoke-induced inflammation and resulting connective tissue breakdown, the precursor of emphysema. The findings support the idea that TNF-α promoter polymorphisms may be of importance in determining who develops smoke-induced chronic obstructive pulmonary disease.