IFN regulatory factor (IRF) 4 is a hematopoietic cell-specific transcription factor that regulates the maturation and differentiation of immune cells. Using an inducible expression system, we found that IRF4 directly induced a specific subset of IFN-stimulated genes (ISGs) in a type I IFN-independent manner in both epithelial and B cell lines. Moreover, Kaposi sarcoma-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) enhances IRF4-mediated gene induction. Coexpression of IRF4 with vFLIP significantly increased ISG60 (IFIT3) and Cig5 (RSAD2) transcription that was dependent on the ability of vFLIP to activate NF-κB. A vFLIP mutant (A57L) defective in NF-κB activation failed to enhance IRF4-mediated ISG induction. Thus, we provide a physiologically relevant mechanism by which viral protein-mediated NF-κB activation modulates specific ISG induction by IRF4. In contrast, IRF4 also acted as a negative regulator of KSHV replication and transcription activator expression after induction of KSHV lytic reactivation in KSHV-positive primary effusion lymphoma cells. Taken together, these results suggest a dual role for IRF4 in regulating ISG induction and KSHV lytic reactivation in primary effusion lymphoma cells.