Telomerase activity is downregulated in somatic cells but is upregulated during the activation of cells of the immune system. The mechanism of this reactivation is not well understood. In this study, we demonstrated that interferon regulatory factor 4 (IRF-4) and, to a lesser extent, IRF-8 induce telomerase activity. The suppression of IRF-4 results in decreased levels of TERT (telomerase reverse transcriptase) mRNA and telomerase activity and reduces cell proliferation. The overexpression of TERT compensates for this proliferation defect, suggesting that telomerase contributes to the regulation of cell proliferation by IRF-4. The induction of telomerase by IRF-4 and IRF-8 correlates with the activation of the TERT promoter. IRF-4 binds the interferon response-stimulated element and the gamma interferon-activated sequence composite binding site in the TERT core promoter region in vivo. Additionally, the binding of Sp1, Sp3, USF-1, USF-2, and c-Myc to the TERT promoter is elevated in cells expressing IRF-4. IRF-4, but not IRF-8, synergistically cooperates with Sp1 and Sp3 in the activation of the TERT promoter. Collectively, these results indicate that IRF-4 and IRF-8, two lymphoid cell-specific transcription factors, increase telomerase activity by activating TERT transcription in immune cells.