Cigarette smoking and aging are major risk factors for chronic obstructive pulmonary disease. An unsolved question is whether elderly lungs are particularly vulnerable to cigarette smoke (CS) exposure. In this study, we tested the hypothesis that aging increases the susceptibility to CS-induced pulmonary inflammation using a mouse model. We subjected 9-week-old and 69-week-old C57BL/6J mice to CS (whole body exposure, 90 min/day), and evaluated neutrophil infiltration in the lungs, the levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage (BAL) fluid, and mRNA expression in bronchiolar epithelium retrieved by laser capture microdissection. The 69-week-old mice showed a greater number of neutrophils and higher levels of bronchiolar KC and MIP-2 expression than 9-week-old mice after 9 days of CS exposure. Furthermore, single CS exposure induced the rapid upregulation of KC and MIP-2 in bronchiolar epithelium in both 9-week-old and 69-week-old mice, and the much higher levels in 69-week-old mice were associated with greater nuclear translocation of nuclear factor-ƒÈB (NF-ƒÈB). In contrast, no age-related differences were observed in the bronchiolar expression of NF-E2-related factor 2-regulated antioxidant and detoxification genes, heme oxygenase-1, NADPH quinine reductase 1 and glutamate-cysteine ligase, modifier unit, or antioxidant activity in BAL fluid, regardless of CS exposure. In summary, aging increases susceptibility to CS-induced inflammation in a mouse model, and robust mRNA upregulation and nuclear translocation of NF-B in bronchiolar epithelium may be involved.