IFNβ plays a critical role in the defense against pathogens viruses through the induction of a broad antiviral transcriptional response. Over the years, studies aimed at depicting the signaling cascade engaged by IFNβ were mainly conducted according to a single cytokine stimulation model. However, a cell is rather subjected simultaneously to several cytokines, which induce a synergistic response different from that initiated by each cytokine individually. Elevated levels of IFNβ and TNFα are found during the host response to pathogens, including virus and bacteria, and also in autoinflammatory and autoimmune diseases. The functional cross-talk between these two cytokines remains poorly known. Recently, we reported that the synergistic action of IFNβ and TNFα produced simultaneously during the infection controls induction of the antiviral DUOX2 gene independently on STAT1 through a STAT2 and IRF9-dependent pathway. In the present study, we aimed to characterize the genome wide transcriptional profile induced in response to IFNβ and TNFα in the absence of STAT1. Taking advantage of STAT1-deficient cells coupled to RNASeq analysis, we found that costimulation with IFNβ and TNFα induces a broad antiviral and immunoregulatory transcriptional program independently of STAT1. Additional sequencing performed following silencing of STAT2 or IRF9 allowed us to show that distinct pathways depending on either STAT2 and IRF9 or on either STAT2 or IRF9 control the expression of IFNβ+TNFα-induced genes. Importantly, we also found that the large majority of differentially induced genes were independent on STAT2 or IRF9. Analysis of the promoter of the STAT1-independent, but STAT2- and IRF9-dependent, CXCL10 gene unveiled a different usage of ISRE sites by the IFNβ and the IFNβ+TNFα pathways. Altogether these observations highlight novel STAT1-independent pathways involved in the establishment of a delayed antiviral and immunoregulatory transcriptional program in conditions where elevated levels of both IFNβ and TNFα are present.