Interferon (IFN) treatment of human fibroblasts induces the transcription of two genes, IFN-IND-1 and -2, to a maximal level between 30 min and 2 h. Continued exposure to IFN results in a “desensitization” characterized by a return to pretreatment levels of transcription and the inability of further IFN treatment to reinduce the transcription of these genes. The imposition and the maintenance of desensitization apparently requires continuous protein synthesis because both can be reversed by cycloheximide. Thus a regulatory circuit of transcription for IFN-IND-1 and -2 includes a prompt IFN-induced transcriptional increase followed shortly by a negative regulatory response requiring a labile protein(s) that limits the duration of the increased transcriptional response.