In addition to direct oncolysis， oncolytic viruses (OVs) also induce antitumor immunity， also called viro-immunotherapy. Limited viral replication and immune-negative feedback are the major hurdles to effective viro-immunotherapy. In this study， we found that use of an adjuvant of fludarabine， a chemotherapeutic drug for chronic myeloid leukemia， increased the replication of Newcastle disease virus (NDV) by targeting signal transducer and activator of transcription 1 (STAT1)， which led to enhanced oncolysis of hepatocellular carcinoma (HCC) cells. Moreover， fludarabine accelerated ubiquitin-proteasomal degradation by enhancing ubiquitylation rather than proteasomal activity. This resulted in accelerated degradation of phosphorylated STAT3 and indoleamine 2， 3-dioxygenase 1 (IDO1)， whose expression was induced by NDV infection. In addition， fludarabine significantly increased the NDV-induced infiltration of NK cells and decreased the number of NDV-induced myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. The aforementioned effects of fludarabine significantly improved NDV-mediated antitumor immunity and prolonged survival in mouse model of HCC. Our findings indicate the utility of fludarabine as an adjuvant for oncolytic anticancer viro-immunotherapy.