Classical swine fever (CSF) caused by virulent strains of classical swine fever virus (CSFV) is a hemorrhagic disease of pigs and is characterized by disseminated intravascular coagulation, thrombocytopenia, and immunosuppression. Until now, the role of the NS2 protein produced by CSFV in the pathogenesis of CSF is not well understood. In this report, we investigated the function of CSFV NS2 by examining its effects on the pro-inflammatory CXC chemokine, interleukin-8 (IL-8) expression, and cell survival. Stable swine umbilical vein endothelial cell line (SUVEC) expressing CSFV NS2 were established and showed that CSFV NS2 expressing SUVEC cells express approximately 16-fold higher levels of IL-8 as compared to control vector GFP-expressing cells, GFP-E2 expressing cells, and untransfected cells. Further studies showed that CSFV NS2 induced endoplasmic reticulum stress and activated the nuclear transcription factor kappa B (NF-κB), which is responsible for the up-regulation of IL-8 and the anti-apoptotic protein, Bcl-2, expression. In addition, the GFPNS2-expressing SUVEC cells were resistant to MG132-induced apoptosis. This study suggested that CSFV NS2 plays an important role in the inflammatory response and in persistent CSFV infection. These findings provide novel information on the function of the poorly characterized CSFV NS2.