The effect of interferon treatment of mouse L cells on the fate of virus messenger RNA following infection with vaccinia virus has been studied. The polyribosomes of interferon-treated, infected cells are found to be disaggregated and it is proposed that htis results from inhibition of the initiation of virus polypeptide snythesis. Evidence is presented that inhibition of polypeptide chain elongation also occurs. The block in initiation appears to be due to the failure of the small ribosome subunit to attach to the virus messenger ribonucleoprotein complex. The translation of the different vaccinia messenger species is inhibited to a comparable extent.