Signal transducer and activator of transcription 2 (STAT2) is best known as a critical transactivator component of the interferon-stimulated gene factor 3 (ISGF3) complex that drives the expression of many interferon (IFN)-inducible genes. However, STAT2 is also involved in DNA binding in non-ISGF3 transcriptional complexes. We used a DNA microarray to survey the expression of genes regulated by IFN-inducible, STAT2-dependent DNA binding, and compared the cDNAs of IFN-treated cells overexpressing intact STAT2 to those of IFN-treated cells overexpressing mutated STAT2 lacking the DNA binding domain. The IFN-inducible expression of genes known to be regulated by ISGF3 was similar in both cases. However, a subset of IFN-inducible genes was identified whose expression was decreased in cells expressing the mutated STAT2. Importantly, these genes all contained gamma-activated sequence (GAS)-like elements in their 5' flanking sequences. Our data reveal the existence of a collection of GAS-regulated target genes whose expression is IFN-inducible and independent of ISGF3 but highly dependent on the STAT2 DNA binding domain. This report is the first analysis of the contribution of the STAT2 DNA binding domain to IFN responses on a global basis, and shows that STAT2 is required for the IFN-inducible activation of the full spectrum of GAS target genes.