Evidence is accumulating for the existence of a STAT2/IRF9-dependent, STAT1-independent IFNα signaling pathway. However, no detailed insight exists in the genome-wide transcriptional regulation and the biological implications of STAT2/IRF9 dependent IFNα signaling as compared to ISGF3. In hST2-U3C and mST2-MS1KO cells we observed that the IFNα-induced expression of OAS2 and Ifit1 correlated with the kinetics of STAT2 phosphorylation, and the presence of a STAT2/IRF9 complex requiring STAT2 phosphorylation and the STAT2 transactivation domain. Subsequent microarray analysis of IFNα treated WT and STAT1 KO cells over-expressing STAT2 extended our observations and identified around 120 known antiviral ISRE-containing ISGs commonly up-regulated by STAT2/IRF9 and ISGF3. The STAT2/IRF9 directed expression profile of these ISGs was prolonged as compared to the early and transient response mediated by ISGF3. In addition, we identified a group of "STAT2/IRF9-specific" ISGs, whose response to IFNα was ISGF3-independent. Finally, STAT2/IRF9 was able to trigger an antiviral response upon EMCV and VSV. Our results further prove that IFNα-activated STAT2/IRF9 induces a prolonged ISGF3-like transcriptome and generates an antiviral response in the absence of STAT1.Moreover, the existence of "STAT2/IRF9-specific" target genes predicts a novel role of STAT2 in IFNα signaling.