Elevated type I interferon (IFN) is believed to be one of the crucial factors involved in the pathogenesis of systemic lupus erythematosus (SLE). Its expression was recently found to be governed by the transcription factor E2F1 which is involved in an autoregulatory triad along with c-Myc and the microRNA polycistron miR-17-92. However, this intricate triad has seldom been investigated in SLE patients. Therefore, the current study was undertaken to investigate the expression pattern of the E2F1/c-Myc/miR-17-5p triad in peripheral blood of SLE patients as well as to examine the impact of manipulating this triad using miR-17-5p mimics and inhibitors on IFN signature in SLE patients.Expression of the E2F1/c-Myc/miR-17-5p triad and the IFN-stimulated gene MxA was analyzed using real time qPCR. Peripheral blood mononuclear cells from SLE patients and controls were transfected with miR-17-5p mimics and antagomirs using the HiPerfect transfection reagent.E2F1 transcripts and miR-17-5p were significantly downregulated while c-Myc and MxA transcripts were significantly upregulated in SLE. Also, transfection of SLE PBMCs with miR-17-5p mimics led to a substantial repression of E2F1 and c-Myc expression. The overall change in this triad upon miR-17-5p mimicking resulted in lowering the transcript levels of the IFN-inducible gene MxA in SLE.This may advocate the manipulation/use of the E2F1/c-Myc/miR-17-5p trinity to effectively control the aberrantly high levels of type I IFN activity in lupus patients.