Uteroglobin (UG, Clara cell secretory protein) is a steroid inducible, multifunctional protein that is secreted by the mucosal epithelia. UG has anti-proliferative and anti-metastatic effects in cancer cells. COX-2, which catalyzes the first step in the synthesis of prostanoids, has been shown to be overexpressed in tumors. This study investigated the effect of UG on the inhibition of COX-2 expression in lung cancer cells. The level of the COX-2 protein and its mRNA were decreased by UG, as demonstrated by Western blot and the RT-PCR, respectively. The EIA shows that UG suppressed PGE2 synthesis. Western blot showed that the NF-kappaB nuclear translocation was inhibited by the transduction of UG. In addition, an EMSA demonstrated the inhibition of the NF-kappaB-DNA binding by UG. The luciferase assay showed that UG also inhibited the NF-kappaB-mediated transcription activity. Furthermore, transfection of the lung cancer cell lines with the COX-2 reporter gene constructs demonstrated that the transcription of COX-2 gene was suppressed by UG. These results show that the inhibition of COX-2 expression by UG transduction correlated with the suppression of NF-kappaB activity in the lung cancer cells. This suggests that UG have the possibility for the treatment of lung cancer.