Classical swine fever is caused by the classical swine fever virus (CSFV), which has a special affinity to endothelial cells. This fever is characterized by hemorrhage and necrosis of vascular injury. Very little information is available on the interaction between vascular endothelial cells and CSFV. In the current report, the cDNA library of swine umbilical vein endothelial cell (SUVEC) was constructed by the switching mechanism at 5' end of the RNA transcript approach. The yeast two-hybrid (Y2H) system was adopted to screen non-structure 2 protein (NS2) interactive proteins in the SUVEC line. Alignment with the NCBI database revealed 11 interactive proteins: GOPC, HNRNPH1, DNAJA1, ATP6, CSDE1, CNDP2, FANCL, TMED4, DNAJA4, MOAP1, and PNMA1. These proteins were mostly related to apoptosis, stress response and oxidation reduction, or metabolism. In the protein interaction network constructed based on proteins with NS2, the more important proteins were MOAP1, DNAJA1, GOPC, FANCL, TMED4, and CSDE1. The interactions detected by the Y2H should be regarded only as preliminary indications. However, the CSFV NS2 interactive proteins in the SUVEC cDNA library obtained in the current study provides valuable information for gaining a better understanding of the host protein-virus interactions of the CSFV NS2 protein.