A number of genes that are induced by type-I interferons are also activated by one or more other inducers, including double-stranded RNA, viruses, interferon-gamma, interleukin-1 and tumor necrosis factor. However, these inducers can also activate the expression of type-I interferons. Thus, the activation of type-I interferon-inducible genes by these other inducers could be direct, or a secondary consequence of the induction of interferon. To distinguish between these possibilities, we have used cell lines lacking all type-I interferon genes to study the direct effect of potential inducers on the expression of 14 interferon-inducible human genes. We show that double-stranded RNA, virus, interferon-gamma or tumor necrosis factor-alpha can act directly to induce specific subsets of type-I interferon-inducible genes in the absence of any possible type-I interferon involvement. The cis-acting element which confers inducibility by type-I interferon has been shown in some cases to confer inducibility by interferon-gamma, double-stranded RNA or virus as well. However, not all promoters containing such an element respond to both interferon and other inducers. Thus, the ability of a given gene to respond to different inducers most likely depends on the exact nature and specific combination of cis-acting elements present in its promoter.