The outcome of a host-pathogen encounter is determined by virulence factors of the pathogen and defense factors of the host. We characterized the impact of host factors (resistant (C57BL/6) or susceptible (BALB/c) genetic background and exposure to IFN-) on transcriptional responses of bone marrow derived macrophages (BMDM) to infection with Yersinia enterocolitica. IFN- treatment more profoundly altered the transcriptome of BMDM than did bacterial infection or genetic background. In BALB/c BMDM, 1161 genes were differentially expressed in response to Yersinia infection with or without IFN- prestimulation. Fourteen genes (1.2%) could only be induced by BALB/c BMDM in response to Yersinia infection after IFN- pretreatment. These genes inhibit apoptosis, activate NFB and Erk signaling, are chemotactic to neutrophils, and are involved in cytoskeletal reorganization, hence possibly in phagocytosis. Ten of these genes possess a common module of binding sites for Hox, Pou and Creb transcription factors in 2 kB of upstream genomic sequence, suggesting a possible novel role of these transcription factors in regulation of immune responses. Fifty-two of 1050 differentially expressed genes (4.9%) were induced more strongly by C57BL/6 BMDM in response to Yersinia infection than in BALB/c BMDM. These genes activate NK cells, have antibacterial properties, or are involved in sensing chemokines and LPS. These data show that host resistance factors modulate a surprisingly small, but identifiable and functionally significant portion of the macrophage transcriptome in response to Yersinia infection.