Transcription factor interferon regulatory factor 5 (IRF5) is a critical mediator of the host immune response to pathogens and cellular response to DNA damage. It has recently been shown to play a role in macrophage polarization, with high levels expressed in M1 (pro-inflammatory) macrophages and low levels in M2 (anti-inflammatory). We previously found that expression IRF5 was down-regulated in the progression of human breast cancer, with loss of IRF5 expression correlating with metastasis. We also found that restoring IRF5 expression in the metastatic human mammary epithelial cell line MDA-MB-231 led to recruitment of CXCR5(+) B and T cells to the tumor. These findings support a role for IRF5 in regulating tumor immunity. In order to directly address the function of IRF5 in the breast cancer microenvironment, we generated syngeneic models of mammary tumorigenesis by orthotopically injecting Irf5+/+ and Irf5-/- 4T1 cells into mammary fat pads of BALB/c mice. Kinetics of tumor formation, growth and metastasis were monitored by bioluminescence imaging and metastasis confirmed by counting metastatic lung nodules. Immune response to Irf5+/+ and Irf5-/-4T1 tumors was studied by comparing tumor-infiltrating leukocyte populations using flow cytometry. Results from this study show that restoring IRF5 expression in 4T1 tumor that normally lacks IRF5 reduces the growth of primary tumor and inhibits metastasis. First, Irf5+/+ tumors were significantly smaller than Irf5-/- tumors. Second, mice baring Irf5+/+ tumors had significantly reduced metastasis than mice with Irf5-/- tumors. Third, the analysis on tumor infiltrating leukocytes showed a significantly larger population of type 2 macrophage and smaller population of CD8+ cytotoxic T cells compared to Irf5+/+ tumors. Thus, we have identified IRF5 as a critical mediator controlling interaction between tumor and the immune system. Our findings point to strategies that enable reprogramming of the tumor-immune microenvironment to enhance anti-tumor immunity and inhibit breast cancer metastasis.