The tumor microenvironment is rich multiple inflammatory cells influenced tumor development. Macrophages infiltrate and secret many cytokines while neoplastic cells forming, which are the most abundant immune cell population present in solid tumors. This microenvironment is a chronic and low-grade inflammation provided a condition for tumor development and angiogenesis. Aspirin has been known as a chemopreventive agent against cancer development. However, it is still a little information about the interaction of aspirin between macrophages and breast cancer cells. This study investigated whether aspirin can regulate inflammation of RAW 264.7 macrophages and then break the crosstalk of 4T1 breast cancer cells. To study the interaction of macrophages and cancer cells, 4T1 cells cultured in RAW 264.7 cells conditioned medium (RAW-CM) and co-cultured model of two cells were used. The cytokines in the cultured supernatants were analyzed by ELISA. When 4T1 cells were cultured in RAW-CM, the cytokine VEGF, PAI-1, TNF-α and IL-6 secretions were significantly increased. After aspirin treatment, MCP-1, PAI-1 and IL-6 productions were decreased. Subsequently, 4T1 cells were co-cultured with RAW264.7 cells and treated with aspirin. The cytokine productions of MCP-1, IL-6 and TGF-β were significantly inhibited. Moreover, the markers of macrophage profile were analyzed, the CD206 was significantly decreased while CD11c was increased at the aspirin treatment in co-culture system, suggested that aspirin treatment tended to M1 macrophages accumulation and blunted tumor suppressed environment, might benefit to against cancer development. In summary, macrophages increase inflammatory microenvironment involved in 4T1 cells growth while aspirin performs apparently suppressive properties through breaking the crosstalk in these two cells by inhibiting neoplastic mediator productions.