The severe acute respiratory syndrome coronavirus (SARS-CoV) is the major causative agent for the worldwide outbreak of SARS in 2003. The mechanism by which SARS-CoV causes atypical pneumonia remains unclear. The nuclear factor kappa B (NF-κB) is a key transcription factor that activates numerous genes involved in cellular immune response and inflammation. Many studies have shown that NF-κB plays an important role in the pathogenesis of lung diseases. In this study, we investigated the possible regulatory interaction between the SARS-CoV nucleocapsid (N) protein and NF-κB by luciferase activity assay. Our results showed that the SARS-CoV N protein can significantly activate NF-κB only in Vero E6 cells, which are susceptible to SARS-CoV infection, but not in Vero or HeLa cells. This suggests that NF-κB activation is cell-specific. Furthermore, NF-κB activation in Vero E6 cells expressing the N protein is dosedependent. Further experiments showed that there is more than one function domain in the N protein responsible for NF-κB activation. Our data indicated the possible role of the N protein in the pathogenesis of SARS.