We have investigated whether IFN-I activates the mTOR translational control pathway and to what extent the control of mRNA translation contributes to IFN α2/β responses. General questions have been addressed by a genome-wide search for IFN-induced genes that are translationally regulated. From this screen, selected candidates have been assessed to interrogate the interplay between transcriptional and post-transcriptional regulation of IFN-induced genes. Translation of the majority of ISG mRNAs was found not to be more sensitive than control mRNAs to mTOR inhibition. Yet, a novel mechanism was described wherein the 5′ UTR of an mRNA is altered in response to IFN-I resulting in a shift from mTOR-insensitive to -sensitive translation.