Classical swine fever virus and bovine virus diarrhea virus are members of the genus pestivirus, which belongs to the family of the Flaviviridae, Recently, envelope glycoprotein E-rns was identified as an RNase, RNases can express different biological actions, They have been shown to be neurotoxic, antihelminthic, and immunosuppressive. We studied the immunosuppressive properties of E-rns in vitro, The glycoprotein totally inhibited concanavalin A induced proliferation of porcine, bovine, ovine, and human lymphocytes, We then studied the direct cytotoxic effects of E-rns on lymphocytes and epithelial cells in protein synthesis assays. E-rns strongly inhibited the protein synthesis of lymphocytes of different species, without cell membrane damage, This suggested an apoptotic process, and indeed apoptosis of lymphocytes was detected after incubation with E-rns, Pestivirus infections are characterized by leukopenia and immunosuppression, Our results suggest that E-rns plays an important role in the pathogenesis of pestiviruses.