Type I IFN regulates different aspects of the immune response, inducing a cell-mediated immunity. We have recently shown that the infection of dendritic cells (DC) with Mycobacterium tuberculosis (Mtb) induces IFN-α. In this work we have monitored a rapid induction of IFN-β followed by the delayed production of the IFN-α1 and/or-α13 subtypes. The Mtb infection rapidly activates the NF-κB complex and stimulates the phosphorylation of IFN regulatory factor (IRF)-3, events known to induce IFN-β expression in viral infection. In turn, the autocrine production of IFN-β induces the IFN-stimulated genes that contain binding sites for activated STATs in their promoters. Among the IFN-stimulated genes induced in DC through STAT activation are IRF-1 and IRF-7. The expression of IRF-1 appears to be dependent on the sequential activation of NF-κB and STAT-1. Once expressed, IRF-1 may further stimulate the transcription of IFN-β. Induction of IRF-7 is also regulated at the transcriptional level through the binding of phosphorylated STAT-1 and STAT-2, forming the IFN-stimulated gene factor-3 complex. In turn, the IRF-1 and IRF-7 expression appears to be required for the delayed induction of the IFN-α1/13 genes. Although correlative, our results strongly support the existence of a cascade of molecular events in Mtb-infected DC. Upon infection, constitutively expressed NF-κB and IRF-3 are activated and likely contribute to the rapid IFN-β expression. In turn, IFN-β-induced IRF-1 and IRF-7 may cooperate toward induction of IFN-α1/13 if infection persists and these factors are activated.