When human diploid cells were induced by Newcastle disease virus (NDV) in the presence of cycloheximide or puromycin, an early interferon was produced up to 4 hr after induction, but was not produced without these reagents. Early interferon production in rabbit kidney cells induced by NDV in the presence of cycloheximide was not observed. This early interferon production was also induced in response to hydroxylamine-treated NDV, ultraviolet light-irradiated NDV and Sepharose-coupled NDV, which had no or low induciblity of late interferon, and was inhibited by pretreatment with actinomycin D. Protein and RNA synthesis were enhanced in the cells which were treated with cycloheximide and then washed out as in the induction process. From these findings it has been suggested that the induction of early interferon synthesis in the cells pulse-treated with protein synthesis inhibitors, was triggered by an interaction between viral envelope and cell membrane.