The lymphotoxin beta receptor (LTbetaR) mediates crucial signals in host defense against intracellular bacteria and viruses. Mice deficient in LTbetaR readily succumb to infections with Listeria monocytogenes, Mycobacterium tuberculosis and murine cytomegalovirus (mCMV). LTbetaR has been shown to be important for the early induction of interferon (IFN) beta after infection with mCMV. However, up to now, it is not known which host effector molecules are induced in cells of the innate immune system after bacterial infections. In order to address this question, comprehensive transcriptome profiling of LTbetaR-deficient and control splenocytes depleted from T and B lymphocytes was performed and differentially regulated genes were identified. Interestingly, a deficiency in IFNalpha- and IFNgamma-mRNA transcription could be found in LTbetaR-deficient cells leading to a marked failure in the immediate up-regulation of IFN controlled genes. These encompass interferon regulatory factors (IRF1 and IRF7), signal transducer activator of transcription (STAT) proteins (STAT1 and STAT2), chemokines, IFN regulated GTPases (IRGs, GBPs), and IFN-induced protein with tetratricopeptide repeats (IFITs). Thus, the immediate LTbetaR-initiated transcriptional response of innate immune cells carries an IFN signature and is responsible for mounting an effective innate immune response to L. monocytogenes.