[Objective] It is important to study the pathogenesis and molecular mechanism how Brucella interacts with host cells. Many researches focus on the regulation of endoplasmic reticulum (ER) stress on the infection and inflammation. Brucella species replicate within host cells in the form of ER-derived vacuoles. The mechanisms by which the bacteria are sequestered into such vacuoles and obtain a continuous membrane supply for their replication remain unclear. To reveal the effect of B. suis S2 on ER stress and the excretion of cytokines in RAW264.7 cells. [Methods] We built an infection model of B. suis S2 using RAW264.7 cells, and detected the expression of GRP78 and CHOP, the makers of endoplasmic reticulum (ER) stress, through real time quantitative PCR (qPCR) and Western blot. We measured cytokines TNF-α, IL-1β and IL-6 via qPCR and ELISA at different intervals after infection. [Results] The optimal MOI used in the infection model was 100:1. Most B. suis S2 were killed during the first 4 to 6 h after they invaded into RAW264.7 cells, then the survived bacteria could reproductive, inducing the apoptosis at 24 h, and necrosis at 48 h. The invasion and reproduction of B. suis S2 increased the expression of GRP78 significantly, causing ER stress of RAW264.7 cells, and decreased the expression of TNF-α, IL-1β and IL-6. [Conclusion] ER stress was involved in the control of B. suis S2 infection in RAW264.7 cells.