Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-kappaB (NF-kappaB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-kappaB activation is not known, although the role of NF-kappaB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-kappaB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-kappaB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-kappaB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of inhibitory subunit of NF-kappaB kinase (IkappaB), as examined by immunocomplex kinase assay, IkappaB phosphorylation, and IkappaB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-kappaB-dependent reporter gene expression. CSC-induced NF-kappaB reporter activity induced by NF-kappaB inducing kinase and IkappaB alpha kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-kappaB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-kappaB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-kappaB and NF-kappaB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.