Many viruses have evolved mechanisms to resist the action of interferon (IFN). These include production of viral gene products that sequester double-stranded RNA (dsRNA) and of small helical RNA. These potentially prevent activation of dsRNA-dependent pathways of IFN action or block expression of cellular genes activated exclusively by dsRNA that may contribute to the antiviral state. Thus, dsRNA might be rate limiting in the development of an IFN-mediated antiviral state. In support of this hypothesis, dsRNA added exogenously to IFN-treated cells in the form of poly(rI):poly(rC) is shown to establish in a dose-dependent manner an antiviral state against two viruses otherwise highly refractory to IFN action, avian reovirus (ARV) and Newcaste disease virus (NDV). Cells exposed singly to high doses of IFN or dsRNA reduced the plaque-forming capacity of these viruses on chicken embryo cells 2-fold. When used in combination, there was up to a 100-fold reduction. In order to abrogate IFN resistance, dsRNA must be added after, not before, an IFN-mediated latent antiviral state is established. dsRNA added exogenously is thought to achieve the threshold required for activation of dsRNA-dependent pathways of IFN action or to induce some dsRNA-stimulated gene whose product acts synergistically with that of some IFN-stimulated gene. The combined sequential treatment with IFN and dsRNA may be useful in overcoming the anti-IFN activity of viruses of clinical interest or in other clinical conditions.