Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD11b+/Gr-1+ cells, proliferation and apoptosis of CD4+ T cells were determined. Arginase activity and arginase-1 (Arg-1) protein expression of splenic CD11b+/Gr-1+ cells, and delayed-type hypersensitivity (DTH) response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD11b+/Gr-1+ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD11b+/Gr-1+ cells. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4+ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.